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  • 1.
    Abrate, Alberto
    et al.
    IRCCS Osped San Raffaele, Italy.
    Buono, Roberta
    IRCCS Osped San Raffaele, Italy.
    Canu, Tamara
    IRCCS Osped San Raffaele, Italy.
    Esposito, Antonio
    IRCCS Osped San Raffaele, Italy.
    Del Maschio, Alessandro
    IRCCS Osped San Raffaele, Italy.
    Luciano, Roberta
    IRCCS Osped San Raffaele, Italy; IRCCS Osped San Raffaele, Italy.
    Bettiga, Arianna
    IRCCS Osped San Raffaele, Italy.
    Colciago, Giorgia
    IRCCS Osped San Raffaele, Italy.
    Guazzoni, Giorgio
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. IRCCS Osped San Raffaele, Italy.
    Altaner, Cestmir
    Slovak Academic Science, Slovakia; St Elisabeth Cancer Institute, Slovakia.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy.
    Cavarretta, Ilaria T. R.
    IRCCS Osped San Raffaele, Italy.
    Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 14, p. 2478-2488Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase:: uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.

  • 2.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Gandaglia, Giorgio
    IRCCS, Italy; Lund University, Sweden.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Fujimura, Tetsuya
    University of Tokyo, Japan.
    Fukuhara, Hiroshi
    University of Tokyo, Japan.
    Montorsi, Francesco
    IRCCS, Italy.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan.
    URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E-2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 117, no 5, p. 821-828Article in journal (Refereed)
    Abstract [en]

    Objective To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E-2 (PGE(2)) instillation in rats. Materials and methods In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE(2)-induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Ad-and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE(2) (50 or 100 mu M) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2, in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence. Results During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE(2)-induced changes in urodynamic variables. PGE(2) increased the SAAs of C-fibres, but not Ad-fibres. URB937 (1 mg/kg) depressed Ad-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE(2). The DRG nerve cells showed strong staining for FAAH, CB1 and CB2, with a mean (SEM) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively. Conclusion The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE(2), suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.

  • 3.
    Aizawa, Naoki
    et al.
    University of Tokyo, Japan.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Fuellhase, Claudius
    University of Munich, Germany.
    Ito, Hiroki
    University of Tokyo, Japan.
    Homma, Yukio
    University of Tokyo, Japan.
    Igawa, Yasuhiko
    University of Tokyo, Japan .
    Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 3, p. 956-963Article in journal (Refereed)
    Abstract [en]

    Purpose: FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Materials and Methods: Female Sprague Dawley (R) rats were anesthetized. Single unit afferent activity of A delta or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP in the L6 dorsal root ganglion were compared by immunofluorescence. Results: A total of 102 single afferent fibers (48 A delta and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean +/- SEM of 78% +/- 9% and of A delta-fibers to a mean of 67% +/- 7% while increasing bladder compliance to a mean of 116% +/- 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity of each fiber type but SR144528 affected only A delta-fiber activity. CGRP positive L6 dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. Conclusions: To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Ad and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

  • 4.
    Albrecht, Knut
    et al.
    Hannover Medical School, Deparment of Legal Medicine, Hannover, Germany.
    Ückert, Stefan
    Hanover Medical School, Department of Urology, Hannover, Germany.
    Oelke, Matthias
    University of Amsterdam, Academic Medical Center (AMC), Department of Urology, Amsterdam, The Netherlands.
    Andersson, Karl-Erik
    Lund University Hospital, Department of Clinical and Experimental Pharmacology, Lund, Sweden.
    Jonas, Udo
    University of Amsterdam, Academic Medical Center (AMC), Department of Urology, Amsterdam, The Netherlands.
    Tröger, Hans-Dieter
    Hannover Medical School, Deparment of Legal Medicine, Hannover, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology.
    Immunohistochemical distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human vagina:: A potential forensic value?2007In: Journal of forensic and legal medicine, ISSN 1752-928X, Vol. 14, no 5, p. 270-274Article in journal (Refereed)
    Abstract [en]

    Objectives

    Phosphodiesterase (PDE) isoenzymes are key proteins involved in the maintenance of the normal function of various tissues of the human body including those of the male and female urogenital tract. More recently, PDEs and their main substrates, cyclic GMP and cyclic AMP, have also been assumed to play a crucial role in the control of the human vagina. In order to elucidate the potential significance of phosphodiesterases as marker proteins in female genital organs, it was the aim of the present study to evaluate by means of immunohistochemistry the distribution of cGMP- and cAMP-PDE isoenzymes in specimens of the human vagina.

    Methods

    Conventional immunohistochemical techniques (double antibody technique, laser fluorescence microscopy) were applied to sections of the human vaginal wall in order to evaluate the presence of the PDE isoenzymes 1, 2, 3, 4, 5 and 10.

    Results

    Immunoreactivities (IR) specific for PDE1 (cAMP/cGMP-PDE, Ca2+/Calmodulin-dependent), PDE2 (cAMP-PDE, cGMP-dependent) and PDE5 (cGMP-PDE) were exclusively registered in the smooth musculature of vaginal arterial vessels, whereas no signals were detected in non-vascular tissue. IR indicating the expression of the cAMP-degrading PDE4 was mainly observed in the vaginal epithelium. Vaginal epithelial cells also presented immunosignals specific for PDE3 (cAMP-PDE, inhibited by cGMP) and PDE10 (dual substrate PDE), nevertheless, these stainings were less abundant than those related to the PDE4. IR for PDE10 was also registered in inflammatory cells located in the subepithelial region of the vaginal wall.

    Conclusion

    Our study revealed the presence of IR specific for PDE1, PDE2, PDE4, PDE5 and PDE10 in sections of the human vagina and demonstrated that these enzymes are not evenly distributed in the tissue. Especially, the prominent expression of the cyclic AMP-PDE4A in the vaginal epithelium may give hint to a potential significance of this isoenzyme as a forensic marker protein. The findings give a rationale to investigate further as to whether the immunohistochemical detection of PDE4 may represent a new forensic tool in order to identify human vaginal epithelial cells.

  • 5.
    Andersson, Karl-Erik
    et al.
    Wake Forest University.
    Gratzke, Christian
    University of Munich.
    Hedlund, Petter
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder2010In: BJU INTERNATIONAL, ISSN 1464-4096, Vol. 106, no 8, p. 1114-1127Article, review/survey (Refereed)
    Abstract [en]

    center dot The transient receptor potential (TRP) channel superfamily has been shown to be involved in nociception and mechanosensory transduction in various organ systems, and studies of the LUT have indicated that several TRP channels, including TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1, are expressed in the bladder, and may act as sensors of stretch and/or chemical irritation. center dot However, the roles of these individual channels for normal LUT function and in LUTS/DO/OAB, have not been established. center dot TRPV1 is the channel best investigated. It is widely distributed in LUT structures, but despite extensive information on morphology and function in animal models, the role of this channel in normal human bladder function is still controversial. Conversely, its role in the pathophysiology and treatment of particularly neurogenic DO is well established. center dot TRPV1 is co-expressed with TRPA1, and TRPA1 is known to be present on capsaicin-sensitive primary sensory neurones. Activation of this channel can induce DO in animal models. center dot TRPV4 is a Ca2+-permeable stretch-activated cation channel, involved in stretch-induced ATP release, and TRPV4-deficient mice exhibit abnormal frequencies of voiding and non-voiding contractions in cystometric experiments. center dot TRPM8 is a cool receptor expressed in the urothelium and suburothelial sensory fibres. It has been implicated in the bladder-cooling reflex and in idiopathic DO. center dot The occurrence of other members of the TRP superfamily in the LUT has been reported, but information on their effects on LUT functions is scarce. There seem to be several links between activation of different members of the TRP superfamily and LUTS/DO/OAB, and further exploration of the involvement of these channels in LUT function, normally and in dysfunction, may be rewarding.

  • 6.
    Andersson, Karl-Erik
    et al.
    Department of Clinical Pharmacology, University of Lund, Sweden.
    Hedlund, Petter
    Department of Clinical Pharmacology, University of Lund, Sweden.
    New directions for erectile dysfunction therapies2002In: International journal of impotence research, ISSN 0955-9930, E-ISSN 1476-5489, Vol. 14 Suppl 1, p. S82-S92Article in journal (Refereed)
    Abstract [en]

    Research in the field of erectile function and dysfunction has continued to expand rapidly. Based on the information available, some directions for future erectile dysfunction therapies can be identified. The first direction is improvement of current therapeutic principles. A second generation of orally active phosphodiesterase (PDE) inhibitors is being introduced, and further developments within this field can be expected. The recent introduction of apomorphine has opened the way for new dopamine receptor agonists. The second direction is combinations of existing therapeutic principles. Combinations of apomorphine and sildenafil and apomorphine and alpha(1)-adrenoceptor (AR) antagonists, for example, seem attractive and may have a therapeutic potential in patients not responding satisfactorily to single-drug treatment. Nitrosylated alpha(1)-AR antagonists, combining nitric oxide donation and alpha(1)- or alpha(2)-AR antagonism, are currently being evaluated. The third direction is new targets within the central nervous system. Melanocortin receptor agonists have shown promise not only in animal models, but also in preliminary studies in humans. Other possible targets, such as growth hormone-releasing peptide receptors, are being explored. The fourth direction is new peripheral targets. Rho-kinase antagonism and non-nitric oxide-mediated stimulation of soluble guanylyl cyclase have been suggested as possible new principles for drug development. The fourth direction is gene therapy. Progress has been made in intracavernosal somatic gene therapy and will probably continue. Still, problems remain, and advantages over conventional pharmacological therapies have to be demonstrated. The final direction is prevention strategies. Strategies to prevent cavernosal degeneration and/or to restore cavernosal function will be one of the most exciting challenges for future research.

  • 7.
    Andersson, Karl-Erik
    et al.
    Lund University Hospital, Sweden.
    Hedlund, Petter
    Lund University Hospital, Sweden.
    Pharmacologic perspective on the physiology of the lower urinary tract2002In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 60, no 5 Suppl 1, p. 13-20Article in journal (Refereed)
    Abstract [en]

    Myogenic activity, distention of the detrusor, and signals from the urothelium may initiate voiding. In the bladder, afferent nerves have been identified not only in the detrusor, but also suburothelially, where they form a plexus that lies immediately beneath the epithelial lining. Extracellular adenosine triphosphate (ATP) has been found to mediate excitation of small-diameter sensory neurons via P2X3 receptors, and it has been shown that bladder distention causes release of ATP from the urothelium. In turn, ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably, not only ATP but also a cascade of inhibitory and stimulatory transmitters and mediators are involved in the transduction mechanisms underlying the activation of afferent fibers during bladder filling. These mechanisms may be targets for future drugs. The central nervous control of micturition involves many transmitter systems, which may be suitable targets for pharmacologic intervention. gamma-Aminobutyric acid, dopamine, enkephalin, serotonin, and noradrenaline receptors and mechanisms are known to influence micturition, and potentially, drugs that affect these systems could be developed for clinical use. However, a selective action on the lower urinary tract may be difficult to obtain. Most drugs currently used for treatment of detrusor overactivity have a peripheral site of action, mainly the efferent (cholinergic) neurotransmission and/or the detrusor muscle itself. In the normal bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis, as well as in the aging bladder, a noncholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions.

  • 8.
    Andersson, Karl-Erik
    et al.
    Wake Forest University, Winston Salem, North Carolina.
    Uckert, Stefan
    Hannover Medical School.
    Stief, Christian
    Ludwig-Maximilian University, Munich.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS2007In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 26, no 6, p. 928-933Article in journal (Refereed)
    Abstract [en]

    Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.

  • 9.
    Andersson, KE
    et al.
    Lund University Hospital.
    Hedlund, Petter
    Lund University Hospital.
    Alm, P
    Lund University Hospital.
    Sympathetic pathways and adrenergic innervation of the penis2000In: International journal of impotence research, ISSN 0955-9930, E-ISSN 1476-5489, Vol. 12, p. S5-S12Article in journal (Refereed)
    Abstract [en]

    The sympathetic nervous system is important for penile function: it mediates detumescence and may contribute to the maintenance of the penis in a non-erect state. The sympathetic preganglionic neurons are found in the intermediolateral gray matter of the spinal cord. Postganglionic neurons are located to the sympathetic chain ganglia, the inferior mesenteric, hypogastric and pelvic ganglia, and possibly to ganglia near the target organ. Sympathetic fibres can be found in the pelvic, cavernous, and pudendal nerves. Stimulation of the sympathetic pathways to the penis may, however, also produce erection. It has been suggested that the suprasacral vasodilator pathway is a sympathetic cholinergic pathway, operating through cholinergic neurons in the pelvic plexus. In the penis, there is a rich sympathetic, adrenergic innervation of the corpus cavernosum (CC) and the vasculature, and in particular of the helicine arteries. Sympathetic, adrenergic nerves also contain neuropeptide Y. Parasympathetic cholinergic nerves, which mediate CC relaxation and erection, contain not only acetylcholine, but also vasoactive intestinal polypeptide, nitric oxide synthase, and probably other mediators and/or mediator-synthesizing enzymes. Activation of sympathetic adrenergic nerves causes release of noradrenaline, acting on alpha-adrenoceptors in the trabecular smooth muscle of the CC and in penile vessels. The role of interactions between different transmitters and mediators, released from nerves or generated locally, in the regulation of contraction and relaxation of CC and penile vessels, needs further study.

  • 10.
    Bauer, Ricarda M.
    et al.
    University of Munich, Germany.
    Strittmatter, Frank
    University of Munich, Germany.
    Gratzke, Christian
    University of Munich, Germany.
    Göttinger, Johanna
    University of Munich, Germany.
    Schlenker, Boris
    University of Munich, Germany.
    Reich, Oliver
    University of Munich, Germany.
    Stief, Christian G.
    University of Munich, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Karl-Erik
    Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, N.C., USA.
    Hennenberg, Martin
    University of Munich, Germany.
    Coupling of α1-adrenoceptors to ERK1/2 in the human prostate2011In: Urologia internationalis, ISSN 0042-1138, E-ISSN 1423-0399, Vol. 86, no 4, p. 427-433Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: α1-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further α1-adrenoceptor functions besides contraction. Here, we investigated whether α1-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2).

    METHODS: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments.

    RESULTS: Stimulation of human prostate tissue with noradrenaline (30 μM) or phenylephrine (10 μM) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 μM) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126.

    CONCLUSIONS: α1-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of α1-adrenoceptors in the regulation of prostate growth.

  • 11.
    Benigni, F
    et al.
    BioXell SpA.
    Baroni, E
    BioXell SpA.
    Zecevic, M
    BioXell SpA.
    Zvara, P
    BioXell SpA.
    Streng, T
    Lund University.
    Hedlund, Petter
    Lund University.
    Colli, E
    BioXell SpA.
    DAmbrosio, D
    BioXell SpA.
    Andersson, KE
    Lund University.
    Oral treatment with a vitamin D3 analogue (BXL628) has anti-inflammatory effects in rodent model of interstitial cystitis2006In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 97, no 3, p. 617-624Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the effects of a vitamin D3 analogue (BXL628) in a model of chronic cystitis, as calcitriol analogues might be an interesting new therapeutic option for interstitial cystitis, for although the cause of the disease remains unclear, the increase in mast cells in the mucosa and detrusor muscle are significant.

    MATERIALS AND METHODS: We devised a mouse model of allergen-induced allergic cystitis that is associated with the up-regulation of genes for interleukin-13, FcepsilonRIalpha and mast cells-derived proteases, a massive inflammatory reaction in the bladder tissue, and augmented levels of mast cell-derived protease 1 (MMCP1) detected in mouse sera.

    RESULTS: Oral administration of BXL628 significantly reduced the expression of interleukin-13, FcepsilonRIalpha and MMCP1 in the bladder. Furthermore, histological analysis showed a decrease in oedema and leukocyte infiltration in the bladder wall. BXL628 treatment reduced serum MMCP1 levels, indicating an effect on mast cell degranulation in vivo.

    CONCLUSIONS: Vitamin D3 analogues may successfully be used as anti-inflammatory agents in allergen-mediated inflammatory reactions. Moreover, the modulatory effect shown on mast cell activation by the BXL628 analogue strongly supports its potential therapeutic use in a possibly mast cell-dependent disease such as human interstitial cystitis.

  • 12.
    Benigni, Fabio
    et al.
    San Raffaele University.
    Hedlund, Petter
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Editorial Material: Reply from Authors re: Apostolos Apostolidis. Taming the Cannabinoids: New Potential in the Pharmacologic Control of Lower Urinary Tract Dysfunction. Eur Urol 2012;61:107-1092012In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 61, no 1, p. 109-111Article in journal (Other academic)
    Abstract [en]

    n/a

  • 13.
    Bivalacqua, Trinity J.
    et al.
    Brady Urological Institute, and Division of Cardiology, Department of Medicine Johns Hopkins Hospital.
    Kendirci, Muammer
    Department of Urology, Tulane University School of Medicine, New Orleans.
    Champion, Hunter C
    Brady Urological Institute, and Division of Cardiology, Department of Medicine Johns Hopkins Hospital.
    Hellstrom, Wayne J G
    Department of Urology, Tulane University School of Medicine, New Orleans.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, Lund University Hospital, Lund.
    Hedlund, Petter
    Lund University Hospital.
    Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1alpha.2007In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 99, no 6, p. 1488-1494Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the expression of cGMP-dependent protein kinase 1 (PKG1)alpha and PKG1beta in the corpus cavernosum, and to evaluate the effect of adenoviral gene transfer of PKG1alpha to the erectile compartment on erectile function in a rat model of diabetes.

    MATERIALS AND METHODS: Diabetic (DM; induced by streptozotocin) male Sprague Dawley rats were transfected with adenoviruses (AdCMVbetagal or AdCMVPKG1alpha, in 10 rats each) 2 months after the induction of DM. Intracavernosal pressure (ICP) during stimulation of the cavernosal nerve (CN) was assessed, and compared with mean arterial pressure (MAP). Erectile tissue was harvested for Western blot analysis, immunohistochemistry and total PKG activity. Ten age-matched rats without DM served as the control.

    RESULTS: Compared to controls, AdCMVbetagal-transfected DM rats had significantly lower peak ICP responses, ICP/MAP ratios, and filling rates during CN stimulation. In DM rats transfected with AdCMVPKG1alpha, peak ICP, ICP/MAP ratios and filling rates were significantly better than in DM rats transfected with the reporter gene. As assessed by Western blot and immunohistochemistry, expression of PKG1alpha and PKG1beta was lower in corporal tissue from DM AdCMVbetagal-transfected rats than in controls. PKG1alpha expression was improved after AdCMVPKG1alpha gene therapy. Total PKG activity was lower in DM rat corporal tissue than in controls, and PKG1alpha gene transfer significantly improved DM corporal PKG activity to a value greater than in the control.

    CONCLUSION: PKG1alpha and PKG1beta activities are reduced in the erectile tissue of the diabetic rat, and gene transfer of PKG1alpha to the penis restored PKG activity and erectile function in vivo in diabetic rats. Gene therapy procedures targeting PKG1alpha might be an interesting future therapeutic approach to overcome diabetic erectile dysfunction resistant to oral pharmacotherapy.

  • 14.
    Brioni, JD
    et al.
    Abbott Laboratories.
    Moreland, RB
    Abbott Laboratories.
    Cowart, M
    Abbott Laboratories.
    Hsieh, GC
    Abbott Laboratories.
    Stewart, AO
    Abbott Laboratories.
    Hedlund, Petter
    Lund University Hospital.
    Donnelly-Roberts, DL
    Abbott Laboratories.
    Nakane, M
    Abbott Laboratories.
    Lynch, JJ
    Abbott Laboratories.
    Kolasa, T
    Abbott Laboratories.
    Polakowski, JS
    Abbott Laboratories.
    Osinski, MA
    Abbott Laboratories.
    Marsh, K
    Abbott Laboratories.
    Andersson, KE
    Lund University Hospital.
    Sullivan, JP
    Abbott Laboratories.
    Activation of dopamine D-4 receptors by ABT-724 induces penile erection in rats2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 17, p. 6758-6763Article in journal (Refereed)
    Abstract [en]

    Apomorphine, a nonselective dopamine receptor agonist, facilitates penile erection and is effective in patients suffering from erectile dysfunction. The specific dopamine receptor subtype(s) responsible for its erectogenic effect is not known. Here we report that the dopamine D(4) receptor plays a role in the regulation of penile function. ABT-724 is a selective dopamine D(4) receptor agonist that activates human dopamine D(4) receptors with an EC(50) of 12.4 nM and 61% efficacy, with no effect on dopamine D(1), D(2), D(3), or D(5) receptors. ABT-724 dose-dependently facilitates penile erection when given s.c. to conscious rats, an effect that is blocked by haloperidol and clozapine but not by domperidone. A proerectile effect is observed after intracerebroventricular but not intrathecal administration, suggesting a supraspinal site of action. s.c. injections of ABT-724 increase intracavernosal pressure in awake freely moving rats. In the presence of sildenafil, a potentiation of the proerectile effect of ABT-724 is observed in conscious rats. The ability of ABT-724 to facilitate penile erection together with the favorable side-effect profile indicates that ABT-724 could be useful for the treatment of erectile dysfunction.

  • 15.
    Buono, Roberta
    et al.
    IRCCS Osped San Raffaele, Italy.
    Briganti, Alberto
    IRCCS Osped San Raffaele, Italy.
    Freschi, Massimo
    IRCCS Osped San Raffaele, Italy.
    Villa, Luca
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    La Croce, Giovanni
    IRCCS Osped San Raffaele, Italy; Lund University, Sweden.
    Moschini, Marco
    IRCCS Osped San Raffaele, Italy.
    Benigni, Fabio
    IRCCS Osped San Raffaele, Italy.
    Castiglione, Fabio
    University of Vita Salute San Raffaele, Italy; Lund University, Sweden.
    Montorsi, Francesco
    IRCCS Osped San Raffaele, Italy; University of Vita Salute San Raffaele, Italy.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates2014In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 744, p. 42-51Article in journal (Refereed)
    Abstract [en]

    Lower urinary tract symptoms (CUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUIS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of siloclosin, a highly selective alpha(1A)-adrenoceptor antagonist, alone or in combination with the phosphocliesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of siloclosin (1 nM-1 mu M) and tadalafil (100 nM-100 mu M) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P less than 0.05), 40-58% (10 nM silodosin+1 mu M tadalafil; P less than 0.001-0.05), 56-67% (100 nM silodosin+10 mu M tadalafil; P less than 0.01-0.05), and 33-55% (1 mu M silodosin+100 mu M tadalafil P less than 0.01-0.05), Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an (alpha(1A)-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.

  • 16.
    Bødker, Anders
    et al.
    Hvidovre Hospital, University of Copenhagen.
    Balslev, Eva
    Hvidovre Hospital, University of Copenhagen.
    Juul, Birgitte Ravn
    Glostrup Hospital, University of Copenhagen.
    Stimpel, Hans
    Glostrup Hospital, University of Copenhagen.
    Meyhoff, Hans-Henrik
    Hillerød Hospital, Denmark.
    Hedlund, Hans
    University of Lund.
    Hedlund, Petter
    University of Lund.
    Iversen, Hans-Georg
    Hvidovre Hospital, University of Copenhagen.
    Andersson, Karl-Erik
    University of Lund.
    Estrogen receptors in the human male bladder, prostatic urethra, and prostate. An immunohistochemical and biochemical study1995In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 29, no 2, p. 161-165Article in journal (Refereed)
    Abstract [en]

    The distribution and quantity of estrogen receptors (ERs) in the human male bladder, prostatic urethra and the prostate were studied in eight males with recurrent papillomas of the bladder or monosymptomatic hematuria (median age 61 years), 14 men undergoing transurethral resection due to benign prostatic hyperplasia (median age 70 years), and nine men undergoing cystectomy due to malignant tumour of the bladder (median age 70 years). In the first group of patients, biopsies for immunohistochemical examination were obtained from the bladder vault, bottom, both side-walls, the trigone area, and the mid-portion of the prostatic urethra, and in the second group from three locations of the prostatic urethra (bladder neck, mid-portion and veramontanum). In the third group, tissue specimens were taken from the vault of the bladder, prostatic urethra, and the prostate, for immunohistochemical as well as biochemical analysis. In the first group, ERs were found in three out of eight specimens of the prostatic urethra, and in one of these, ERs were confined to periurethral glands. ERs could not be demonstrated in any of the bladder-biopsies. In the second group, ERs were not found in the bladder neck, but were seen in four preparations from the veramontanum and in two from the midportion of the urethra. ERs were located in the urothelium and periurethral glands. In the third group, ERs were seen immunohistochemically in the prostatic urethra (two cases) and the prostatic stromal tissue (two cases). ERs could be demonstrated in the bladder neither by immunohistochemistry nor biochemically.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 17.
    Carringer, M
    et al.
    Örebro Medical Centre.
    Hedlund, Petter
    Lund University Hospital.
    Pedersen, J
    Örebro Medical Centre.
    Autonomic innervation of vas deferens after autotransposition - A functional study in the rat1997In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 31, no 6, p. 523-528Article in journal (Refereed)
    Abstract [en]

    In order to investigate the nerve-mediated response of vas deferens subjected to autotransposition, muscular strips were taken from various segments of rat vas. Electrical field stimulation (EFS) was applied and frequency-response curves were determined. After autotransposition the neural function was preserved, albeit the amplitude of the contractile response to EFS was smaller than in controls. Further, a reduced contractile response was noted in the vas segments proximal, as well as distal, to the transposed segment, probably due to secondary reactions to the surgical trauma. Noradrenaline and ATP seem to act as transmitter substances in the transposed vas segments because the results show a reduction of the contraction after pretreatment with prazosin or α,β-methylene ATP. However, the reduction recorded was less pronounced in transposed segments of vas compared with controls, indicating that other transmitter substances may contribute. No difference in contractile response could be seen between segments from fertile rats and segments from infertile animals and it is concluded that factors other than the intrinsic neural response determine fertility after autotransposition of vas.

  • 18.
    Castiglione, Fabio
    et al.
    San Raffaele University, Italy .
    Bergamini, Alice
    San Raffaele University, Italy .
    Bettiga, Arianna
    San Raffaele University, Italy .
    Bivalacqua, Trinity J.
    Johns Hopkins University, MD, USA .
    Benigni, Fabio
    San Raffaele University, Italy .
    Strittmatter, Frank
    Munich University, Germany.
    Gandaglia, Giorgio
    San Raffaele University, Italy .
    Rigatti, Patrizio
    San Raffaele University, Italy .
    Montorsi, Francesco
    San Raffaele University, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Perioperative Betamethasone Treatment Reduces Signs of Bladder Dysfunction in a Rat Model for Neurapraxia in Female Urogenital Surgery2012In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 62, no 6, p. 1076-1085Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available.

    OBJECTIVE:

    To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model.

    DESIGN, SETTING, AND PARTICIPANTS:

    Female Sprague-Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

    Western blot, immunohistochemistry, organ bath experiments, and cystometry.

    RESULTS AND LIMITATIONS:

    Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 ± 2 cm H(2)O compared with 21 ± 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats.

    CONCLUSIONS:

    PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function.

  • 19.
    Castiglione, Fabio
    et al.
    Hospital San Raffaele, Italy .
    Bergamini, Alice
    Hospital San Raffaele, Italy .
    Russo, Andrea
    Hospital San Raffaele, Italy .
    La Croce, Giovanni
    Hospital San Raffaele, Italy .
    Castagna, Giulia
    Hospital San Raffaele, Italy .
    Colciago, Giorgia
    Hospital San Raffaele, Italy .
    Salonia, Andrea
    Hospital San Raffaele, Italy .
    Rigatti, Patrizio
    Hospital San Raffaele, Italy .
    Montorsi, Francesco
    Hospital San Raffaele, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. Hospital San Raffaele, Italy .
    Inhibition of Phosphodiesterase 4 Enhances Clitoral and Vaginal Blood Flow Responses to Dorsal Clitoral Nerve Stimulation or PGE1 in Anesthetized Female Rats2013In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 10, no 4, p. 939-950Article in journal (Refereed)
    Abstract [en]

    Introduction. Cyclic adenosine 35 monophosphate (cAMP) is produced by adenylate cyclase after activation by, e.g., vasoactive intestinal polypeptide or prostaglandin E1 (PGE1). The cAMP-degrading phosphodiesterase 4 (PDE4) is expressed in the vagina and clitoris, but no information is available on the functional role for PDE4-related signals in the female neurovascular genital response. Aim. The aim of this study is to study the effect of inhibition of PDE4 with rolipram on nerve- and PGE1-induced vaginal and clitoral blood flow responses of rat. Methods. Measure of clitoral and vaginal blood flow and blood pressure in anesthetized rats during activation of the dorsal clitoral nerve (DCN) before and after intraperitoneal administration of rolipram or sildenafil (phosphodiesterase type 5 inhibitors [PDE5]) and nitro-L-arginine (L-NNA) (nitric oxide synthase inhibitor). Effect by topical administration of PGE1 on genital blood flow was also evaluated. Main Outcome Measure. Blood flow was recorded as tissue perfusion units (TPU) by a Laser Doppler Flowmeter. Mean arterial blood pressure (MAP) was recorded (cmH2O) in the carotid artery. Blood flow responses are expressed as TPU/MAP. Unpaired t-test and an analysis of variance were used. Results. Compared with control stimulations, rolipram (0.3mg/kg) caused a twofold increase in peak blood flow (Pandlt;0.05) and fourfold increase of the rate of clitoral blood flow during activation of the DCN (Pandlt;0.05). Simultaneously, a twofold increase in peak blood flow and threefold increase in rate of blood flow were noted in the vagina (Pandlt;0.05). Similar effects were noted for sildenafil (0.2mg/kg) (Pandlt;0.05). Inhibitory effects by L-NNA (60mg/kg) on blood flow responses to DCN activation were significantly lower for rats treated with rolipram than with sildenafil (Pandlt;0.05). PGE1-induced (10g) blood flow responses were significantly higher (Pandlt;0.05) in rats treated with rolipram than with sildenafil. Conclusions. These findings suggest that the cAMP/PDE4 system may be of similar functional importance as the nitric oxide/cyclic guanosine monophosphate/PDE5 pathway for neurovascular genital responses of the female rat. Castiglione F, Bergamini A, Russo A, La Croce G, Castagna G, Colciago G, Salonia A, Rigatti P, Montorsi F, and Hedlund P. Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats. J Sex Med 2013; 10: 939-950.

  • 20.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics. University of Vita Salute San Raffaele, Italy .
    Van der Aa, Frank
    University of Louvain, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, MD USA .
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Italy .
    Van Poppel, Hein
    University of Louvain, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Italy .
    De Ridder, Dirk
    University of Louvain, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Italy .
    Correction: Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronies Disease (vol 63, pg 551, 2013)2013Other (Refereed)
    Abstract [en]

    n/a

  • 21.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Milan, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Van der Aa, Frank
    Katholieke University of Leuven, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, Baltimore, MD, USA.
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Milan, Italy .
    Van Poppel, Hein
    Katholieke University of Leuven, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Milan, Italy .
    De Ridder, Dirk
    Katholieke University of Leuven, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Milan, Italy .
    Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronies Disease2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 3, p. 551-560Article in journal (Refereed)
    Abstract [en]

    Background: Peyronies disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. less thanbrgreater than less thanbrgreater thanObjective: To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. less thanbrgreater than less thanbrgreater thanDesign, setting, and participants: A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 50-mu g transforming growth factor (TGF)-beta 1 in a 50-mu l vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. less thanbrgreater than less thanbrgreater thanIntervention: The sham and PD groups were treated 1 d after TGF-beta 1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-mu l vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. less thanbrgreater than less thanbrgreater thanOutcome measurements and statistical analysis: The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. less thanbrgreater than less thanbrgreater thanResults and limitations: Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p = 0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. less thanbrgreater than less thanbrgreater thanConclusions: This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum.

  • 22.
    Castiglione, Fabio
    et al.
    University of Vita Salute San Raffaele, Milan, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Van der Aa, Frank
    Katholieke University of Leuven, Belgium .
    Bivalacqua, Trinity J.
    Johns Hopkins Medical Institute, MD USA .
    Rigatti, Patrizio
    University of Vita Salute San Raffaele, Italy .
    Van Poppel, Hein
    Katholieke University of Leuven, Belgium .
    Montorsi, Francesco
    University of Vita Salute San Raffaele, Milan, Italy .
    De Ridder, Dirk
    Katholieke University of Leuven, Belgium .
    Albersen, Maarten
    University of Vita Salute San Raffaele, Milan, Italy .
    Reply from Authors re: Ching-Shwun Lin, Tom F. Lue. Adipose-derived Stem Cells for the Treatment of Peyronie's Disease? Eur Urol 2013;63:561–2: Xenogeneic Adipose Stem Cell Treatment in a Rat Model of Peyronie's Disease2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 3, p. 563-564Article in journal (Other academic)
  • 23.
    Castiglione, Fabio
    et al.
    Urol Research Institute, Milan.
    Russo, Andrea
    Urol Research Institute, Milan.
    Salonia, Andrea
    Urol Research Institute, Milan.
    Rigatti, Patrizio
    Urol Research Institute, Milan.
    Montorsi, Francesco
    Urol Research Institute, Milan.
    Hedlund, Petter
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    SILDENAFIL AND ROLIPRAM ENHANCE CLITORAL AND VAGINAL BLOOD FLOW RESPONSES TO DORSAL CLITORAL NERVE STIMULATION IN ANESTHETIZED FEMALE RATS in JOURNAL OF SEXUAL MEDICINE, vol 7, issue , pp 119-1192010In: JOURNAL OF SEXUAL MEDICINE, Blackwell Publishing Ltd , 2010, Vol. 7, p. 119-119Conference paper (Refereed)
    Abstract [en]

    n/a

  • 24.
    Dizeyi, N
    et al.
    Department of Urology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Bjartell, A
    Department of Urology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Hedlund, Petter
    Department of Clinical Pharmacology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Taskén, K A
    Oslo Urological University Clinic, Aker University Hospital, Faculty Division Aker University Hospital, University of Oslo, Oslo, Norwaytal, Faculty Division Aker University Hospital, University of Oslo.
    Gadaleanu, V
    Department of Pathology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Abrahamsson, P-A
    Department of Urology, Malmö University Hospital, Lund University, Malmö, Sweden.
    Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines.2005In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 47, no 6, p. 895-900Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Overexpression of receptors to neuroendocrine (NE) cell products has been suggested to contribute to development of hormone-refractory prostate cancer (HRPC). In this study, we evaluated the expression of 5-HTR2B and 5-HTR4 in HRPC, and the effects of their antagonist on PC cell line growth.

    METHODS: Proteins and mRNA expression was determined by immunohistochemistry, western blot and RT-PCR. Growth inhibition of PC cell lines was determined in vitro using ELISA-BrdU proliferation assay and cell cycle was evaluated by flow cytometry.

    RESULTS: Immunostaining of 5-HTR2B was observed in low-grade and high-grade tumours, PIN and BPH cells, and in vascular endothelial cells, whereas 5-HTR4 was found predominantly in high-grade tumours. This result was confirmed by western blot analysis. At the mRNA level, 5-HTR4 mRNA was expressed in DU145 and LNCaP cells. Antagonists to both receptor subtypes inhibited proliferation of PC cells in a dose-dependent manner.

    CONCLUSIONS: The present result indicate that 5-HTRs are present at various tumour stages and that antagonists to these receptors can inhibit the proliferative activity of androgen-independent PC cell lines.

  • 25.
    Dizeyi, Nishtman
    et al.
    Malmö University Hospital, Lund University, Malmö.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bjartell, Anders
    Malmö University Hospital, Lund University, Malmö.
    Tinzl, Martina
    Malmö University Hospital, Lund University, Malmö.
    Austild-Taskén, Kristin
    Oslo Urological University Clinic, Aker University Hospital, University of Oslo, Norway.
    Abrahamsson, Per-Anders
    Malmö University Hospital, Lund University, Malmö.
    Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines2011In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 29, no 4, p. 436-445Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells.

    METHODS: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively.

    RESULTS: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression.

    CONCLUSIONS: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.

  • 26.
    Drake, M.
    et al.
    Urological Institute, Southmead Hospital, Bristol, UK.
    Gillespie, J.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Harvey, I.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Lagou, M.
    University of Newcastle, Newcastle-upon-Tyne, UK.
    Andersson, K-E
    Lund University Hospital.
    Muscarinic stimulation of the rat isolated whole bladder: pathophysiological models of detrusor overactivity2006In: Autonomic & Autacoid Pharmacology, ISSN 1474-8665, E-ISSN 1474-8673, Vol. 26, no 3, p. 261-266Article in journal (Refereed)
    Abstract [en]

    1 Hypotheses as to the pathophysiological basis of bladder detrusor muscle overactivity (DO) have identified both central nervous and peripheral mechanisms as likely contributory factors. In this paper, we describe peripheral autonomous bladder activity in two animal models of DO and discuss how the differences observed between the two models support the likelihood that clinical DO has a multifactorial basis. 2 A total of 12 adult female Sprague-Dawley rats underwent obstruction or sham operation for 1 or 4 weeks. Six adult female spontaneously hypertensive rats (SHR) were compared with normal Wistar controls. Bladders were microsurgically removed and mounted in whole organ tissue baths. Recordings of intravesical pressure in response to the muscarinic receptor agonist arecaidine were performed under standardized conditions. 3 In the partially obstructed rat bladder, the amplitude of pressure fluctuations elicited by the muscarinic agonist arecaidine was significantly increased compared with sham-operated animals. The tonic component of the response was no different for the two groups. No difference from controls was apparent in the SHR. 4 We conclude that alterations in autonomous bladder activity in the obstructed rat model suggest that peripheral functional changes contribute to the pathophysiological abnormality. In contrast, the fundamental abnormality in the SHR appears to be at a more central level. The observations support the supposition that lesions at widely separate sites can give rise to apparently similar abnormalities of lower urinary tract function.

  • 27.
    Drake, Marcus J
    et al.
    Tyne Micturution Research Group, School of Surgical Sciences, University of Newcastle, United Kingdom..
    Hedlund, Petter
    Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, University of Lund, Sweden..
    Brading, Alison F
    Hussain, Iqbal
    Fowler, Clare
    Landon, David N
    Morphology, phenotype and ultrastructure of fibroblastic cells from normal and neuropathic human detrusor: absence of myofibroblast characteristics.2003In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 169, no 4, p. 1573-6Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Fibroblasts are functionally diverse and fibroblastic cells with smooth muscle-like characteristics (myofibroblasts) regulate smooth muscle activity in certain tissues. The presence of myofibroblasts has been reported in the bladder with important implications for normal function and detrusor overactivity. We assessed fibroblastic cell characteristics to discern features suggesting a myofibroblast phenotype in normal or neuropathic human detrusor.

    MATERIALS AND METHODS: A total of 25 control samples were obtained from cadaveric organ donors or patients with a mean age of 42.3 years investigated for hematuria and compared with samples from 18 patients with a mean age of 37.4 years with neurogenic detrusor overactivity. Morphology, phenotypic expression of various markers and the ultrastructure of each fibroblastic cell visible in multiple sections from each specimen was evaluated by 2 independent assessors.

    RESULTS: Fibroblastic cells were observed throughout the smooth muscle and connective tissue. They were located peripherally on muscle fascicles and had a polar stellate appearance with processes ramifying in interfascicular planes and muscle. They possessed vimentin-like immunoreactivity and weak c-kit-like immunoreactivity but not desmin or alpha-smooth muscle actin-like immunoreactivity. Ultrastructurally they showed dilated rough endoplasmic reticulum with a moderately electron dense amorphous content and prominent golgi complexes. Nuclei had clumped peripheral heterochromatin. There were extensive flattened processes that lacked basal laminae. There was no specific contact with nerve fibers or smooth muscle. Neuropathic bladder samples did not differ overtly from those of controls.

    CONCLUSIONS: The detrusor possesses an extensive network of fibroblastic cells and processes. No evidence of myofibroblast differentiation was discerned in normal or neuropathic detrusor, although a minority subpopulation or regional variability in cellular phenotype could not be excluded.

  • 28.
    Drake, Marcus J
    et al.
    Urophysiology Research Group , School of Surgical Sciences, University of Newcastle, United Kingdom.
    Hedlund, Petter
    Department of Clinical Pharmacology, Lund University Hospital, Sweden.
    Harvey, Ian J
    Urophysiology Research Group , School of Surgical Sciences, University of Newcastle, United Kingdom.
    Pandita, Raj Kumar
    Department of Clinical Pharmacology, Lund University Hospital, Sweden.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, Lund University Hospital, Sweden.
    Gillespie, James I
    Urophysiology Research Group , School of Surgical Sciences, University of Newcastle, United Kingdom.
    Partial outlet obstruction enhances modular autonomous activity in the isolated rat bladder.2003In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 170, no 1, p. 276-279Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Autonomous bladder activity can take the form of localized micromotions (MMs), suggesting that the detrusor may be arranged into component modules, of which each is capable of contracting autonomously. We examined MMs in isolated whole rat bladder and the effects of partial bladder outlet obstruction as a model of detrusor overactivity (DO) to ascertain whether altered modular activity could be an etiological factor in DO.

    MATERIALS AND METHODS: A total of 12 adult female Sprague-Dawley rats underwent obstruction or sham operation for 1 or 4 weeks. Bladders were microsurgically removed and mounted in whole organ tissue baths. Recordings of intravesical pressure and simultaneous registration of intramural contractions were performed under standardized conditions.

    RESULTS: Prior to filling MMs took the form of localized contractions near the vesicoureteral junction in sham operated animals and multifocal microcontractions in obstructed animals. Intravesical volume increases were associated with a change in localized MMs to propagated contraction waves. In sham operated animals stretch resulted in increased MM frequency but decreased amplitude. After obstruction stretch elicited highly coordinated MMs and enhanced intravesical pressure transmission. The time since surgery did not alter observations in the sham or obstructed group.

    CONCLUSIONS: Detrusor muscle in isolated bladders under conditions modeling urine storage may have a functional modular arrangement with the basolateral region most active prior to filling. Peripheral factors determining intravesical pressure include the number of modules active, coordination and intramural tension at other sites. After bladder outlet obstruction more modules are active at baseline and their coordination is enhanced by stretch, leading to increased pressure fluctuations. Such changes may contribute to the development of DO.

  • 29.
    Drake, Marcus J
    et al.
    Oxford Continence Group, University Department of Pharmacology, Oxford, United Kingdom.
    Hedlund, Petter
    Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Mills, Ian W
    Oxford Continence Group, University Department of Pharmacology, Oxford, United Kingdom.
    McCoy, Rachel
    Oxford Continence Group, University Department of Pharmacology, Oxford, United Kingdom.
    McMurray, Gordon
    Oxford Continence Group, University Department of Pharmacology, Oxford, United Kingdom.
    Gardner, Brian P
    National Spinal Injury Centre, Stoke Mandeville, Aylesbury, United Kingdom.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Brading, Alison F
    Oxford Continence Group, University Department of Pharmacology, Oxford, United Kingdom.
    Structural and functional denervation of human detrusor after spinal cord injury.2000In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 80, no 10, p. 1491-9Article in journal (Refereed)
    Abstract [en]

    The bladder receives an extensive nerve supply that is predominantly cholinergic, but several putative transmitters are present, some of which are colocalized. Previous studies have shown increased levels of sensory nerves, reduced inhibitory transmitters, and structural and functional changes in the excitatory input in unstable bladder conditions. The present study compared the end-organ nerve supply to the bladder in spinal cord injury (SCI) with uninjured controls. Acetylcholinesterase histochemistry and double-label immunofluorescence were used to investigate neurotransmitter content, with confocal laser scanning microscopy to assess colocalization. Organ bath studies provided functional correlates for the structural changes in the excitatory innervation. Control samples had dense innervation of the detrusor containing a diverse range of transmitters. Hyperreflexic SCI samples showed patchy denervation, and areflexic SCI samples were diffusely denervated. Vasoactive intestinal polypeptide-, neuropeptide Y-, neuronal nitric oxide synthase-, and galanin-immunoreactive nerve fibers were reduced from frequent or moderately frequent to infrequent or very infrequent in SCI. Calcitonin gene-related peptide-immunoreactive fibers were infrequent in controls and SCI samples. Patterns of colocalization were unchanged, but significantly fewer fibers expressed more than one transmitter. The subepithelial plexus was markedly reduced and several of the smaller coarse nerve trunks showed no immunoreactivity to the transmitters assessed. There was no reduction in sensitivity to electrical field stimulation of intrinsic nerves in SCI, but the maximum force generated by each milligram of bladder tissue and the peak force as a proportion of the maximum carbachol contraction were significantly reduced and the responses were protracted. There was no significant functional atropine-resistant neuromuscular transmission in controls or SCI. The reported findings have clinical implications in the management of chronic SCI and development of new treatments.

  • 30.
    Fuellhase, Claudius
    et al.
    University of Munich, Germany .
    Russo, Andrea
    San Raffaele University, Italy .
    Castiglione, Fabio
    San Raffaele University, Italy .
    Benigni, Fabio
    San Raffaele University, Italy .
    Campeau, Lysanne
    Wake Forest University, NC USA .
    Montorsi, Francesco
    San Raffaele University, Italy .
    Gratzke, Christian
    University of Munich, Germany .
    Bettiga, Arianna
    San Raffaele University, Italy .
    Stief, Christian
    University of Munich, Germany .
    Andersson, Karl-Erik
    Wake Forest University, NC USA .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats2013In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 189, no 6, p. 2364-2370Article in journal (Refereed)
    Abstract [en]

    Purpose: We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. Materials and Methods: We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. Results: Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. Conclusions: FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.

  • 31.
    Fuellhase, Claudius
    et al.
    University of Rostock, Germany; University of Munich, Germany.
    Schreiber, Andrea
    University of Munich, Germany; University of Munich, Germany.
    Giese, Armin
    University of Munich, Germany.
    Schmidt, Michael
    University of Munich, Germany.
    Montorsi, Francesco
    University of Milan, Italy; University of Vita San Raffaele, Italy.
    Gratzke, Christian
    University of Munich, Germany.
    La Croce, Giovanni
    University of Milan, Italy; Lund University, Sweden.
    Castiglione, Fabio
    University of Vita San Raffaele, Italy; Lund University, Sweden.
    Stief, Christian
    University of Munich, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. University of Milan, Italy.
    Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats2016In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 35, no 4, p. 464-470Article in journal (Refereed)
    Abstract [en]

    AimsTo test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. MethodsMale rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5g rimonabant (CB1 antagonist) or 5g SR144528 (CB2 antagonist) were studied in awake rats. ResultsAfter administration of rimonabant or SR144528, non-obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. ConclusionsUrodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. (c) 2015 Wiley Periodicals, Inc.

  • 32.
    Gandaglia, G.
    et al.
    San Raffaele Scientific Institute, Milan, Italy.
    Strittmatter, F.
    Lund University, Sweden.
    La Croce, G.
    San Raffaele Scientific Institute, Milan, Italy.
    Benigni, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Bettiga, A.
    San Raffaele Scientific Institute, Milan, Italy.
    Castiglione, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Moschini, M.
    San Raffaele Scientific Institute, Milan, Italy.
    Mistretta, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Gratzke, C.
    Munich University, Germany.
    Montorsi, F.
    San Raffaele Scientific Institute, Milan, Italy.
    Stief, C.
    Munich University, Germany.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats2014In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 33, no 8, p. 1251-1258Article in journal (Refereed)
    Abstract [en]

    AIMS:

    To study micturition and bladder overactivity in female rats after chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA).

    METHODS:

    Sprague-Dawley rats received daily subcutaneous injections of OEtA (0.3 mg/kg), or vehicle for 2 weeks. Cystometries, organ bath studies, Western blot, and immunofluorescence were then used. Expressions of FAAH, cannabinoid 1 and 2 receptors (CB1 and CB2), mitogen-activated protein kinase (MAPK), vesicular acetyl choline-transporter protein (VAChT), and calcitonin gene-related peptide (CGRP) were evaluated.

    RESULTS:

    At baseline, OEtA-treated rats had higher values (P < 0.05) of micturition intervals (MI) and volumes (MV), bladder capacity (BC), threshold pressure, and flow pressure than vehicle controls. Intravesical PGE2 reduced MI, MV, and BC, and increased basal pressure and the area under the curve in all rats. However, these urodynamic parameters were altered less by intravesical PGE2 in OEtA-treated rats (P < 0.05 vs. vehicle controls). Compared to vehicle controls, detrusor from OEtA-treated rats had larger contractions to carbachol at 10-0.1 µM, but no difference in Emax was recorded. FAAH, CB1, CB2, VAChT, or CGRP was similarly expressed in bladders from all rats. In separate experiments, intravesical OEtA increased mucosal expression of phosphorylated MAPK.

    CONCLUSIONS:

    Chronic FAAH inhibition altered sensory urodynamic parameters and reduced bladder overactivity. Even if it cannot be excluded that OEtA may act on central nervous sensory pathways to contribute to these effects, the presence of FAAH and CB receptors in the bladder and activation of intracellular signals for CB receptors by intravesical OEtA suggest a local role for FAAH in micturition control. Neurourol. Urodynam

  • 33.
    Giuliano, Francois
    et al.
    Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France.
    Pfaus, James
    Psychology, Concordia University, Montreal, Quebec, Canada.
    Balasubramanian, Srilatha
    Department of Obstetrics and Gynecology, National University Hospital of Singapore, Singapore.
    Hedlund, Petter
    Department of Clinical Chemistry and Pharmacology, Lund University Hospital, Lund, Sweden.
    Hisasue, Shin-ichi
    Urology, Sapporo Medical University, Sapporo, Japan.
    Marson, Lesley
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Wallen, Kim
    Psychology, Emory University, Atlanta, GA, USA.
    Experimental models for the study of female and male sexual function.2010In: The journal of sexual medicine, ISSN 1743-6109, Vol. 7, no 9, p. 2970-2995Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Significant progress has been made in the understanding of physiological and pharmacological mechanisms of human sexual functioning through preclinical research in animal models.

    AIM: To provide an evidence-based documentation of the experimental models evaluating male and female sexual function for useful clinical translation.

    METHODS: Consensus discussion over the past 18 months leading to summarized views of seven experts from six countries.

    MAIN OUTCOME MEASURE: Report was based on the critical analysis of scientific information available in literature and subcommittee presentations, discussions, and exchanges of ideas and feedback.

    RESULTS: Fundamental research in animal models has led to considerable understanding of the physiological mechanisms underlying desire, arousal, genital, and other sexual responses and the design of rational pharmacological treatments for certain sexual dysfunctions in the male and female. Tissue and cellular in vitro systems have provided critical information on the in vivo interactions and modulations in the presence and absence of chemical, biological, vascular, neurologic, endocrine, and genetic inputs. The animal models seem indispensable for elucidating the biophysiological and etiopathological aspects of male and female sexual disorders.

    CONCLUSIONS: Useful insights into the human experience have been derived from basic research in ways that are far more difficult to obtain in humans, both scientifically and ethically. The animal model with a good predictive value can be used as a successful preclinical tool so long as the functional end points are homologous or analogous. The key issue is whether further evaluations are warranted to extrapolate the results in a clinical setting.

  • 34.
    Gomez-Pinilla, Pedro J
    et al.
    - Spanien.
    Gomez, Maria F
    Lund.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Swärd, Karl
    Lund.
    Hellstrand, Per
    Lund.
    Camell, Pedro J
    Spanien.
    Pozo, Maria J
    Spanien.
    Andersson, Karl-Erik
    Lund/North Carolina.
    Effect of melatonin on age associated changes in guinea pig bladder function2007In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 177, p. 1558-1561Article in journal (Refereed)
    Abstract [en]

    Purpose

    The incidence of urinary incontinence increases with age but the cause and effect relationship between aging and altered bladder function is poorly understood. It was suggested that melatonin can ameliorate negative effects induced by aging by its free radical scavenging activity and its ability to decrease oxidative stress. We investigated the changes in bladder function evoked by aging and the possible benefits of melatonin treatment on age related bladder disturbances.

    Materials and Methods

    Bladder function was assessed using cystometry in conscious, freely moving female guinea pigs. Animals were grouped according to age as young adults (4 months old) and senescents (18 to 20 months old). A group of senescent animals were treated with 2.5 mg kg−1 day−1 melatonin for 21 days.

    Results

    Aging led to increased detrusor activity, as demonstrated by short micturition intervals, decreased bladder capacity and spontaneous contractions during the filling phase. During the voiding phase aged animals showed lower micturition pressures than young adults. Melatonin counteracted the cystometric changes in senescent animals and restored micturition parameters to those of young adults.

    Conclusions

    These results show that in guinea pigs aging induces detrusor overactivity. Melatonin treatment improved age induced changes in bladder function. If similar effects can be demonstrated in humans, melatonin treatment may be a new approach to decrease the impact of age related bladder disorders.

  • 35.
    Gomez-Pinilla, Pedro J.
    et al.
    University of Extremadura.
    Gomez, Maria F.
    Lund University.
    Sward, Karl
    Lund University.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hellstrand, Per
    Lund University.
    Camello, Pedro J.
    University of Extremadura.
    Andersson, Karl-Erik
    Lund University.
    Pozo, Maria J.
    University of Extremadura.
    Melatonin restores impaired contractility in aged guinea pig urinary bladder2008In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 44, no 4, p. 416-425Article in journal (Refereed)
    Abstract [en]

    0

  • 36.
    Gratzke, Christian
    et al.
    University Lund Hospital, Department Clin Chemistry and Pharmacol, S-22185 Lund, Sweden Ludwig Maximilians University Hospital, Department Urol, Munich, Germany Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Christ, George J
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Stief, Christian G
    Ludwig Maximilians University Hospital, Department Urol, Munich, Germany .
    Andersson, Karl-Erik
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Localization and Function of Cannabinoid Receptors in the Corpus Cavernosum: Basis for Modulation of Nitric Oxide Synthase Nerve Activity2010In: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 57, no 2, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10(-9) to 10(-4) M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mu M) inhibited electrically evoked smooth-muscle relaxations (34-48%; p andlt;= 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.

  • 37.
    Gratzke, Christian
    et al.
    Wake Forest Institute.
    Streng, Tomi
    Turku University.
    Park, Anthony
    Wake Forest Institute.
    Christ, George
    Wake Forest Institute.
    Stief, Christian G
    University Munich.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Karl-Erik
    Wake Forest Institute.
    Distribution and Function of Cannabinoid Receptors 1 and 2 in the Rat, Monkey and Human Bladder2009In: JOURNAL OF UROLOGY, ISSN 0022-5347, Vol. 181, no 4, p. 1939-1948Article in journal (Refereed)
    Abstract [en]

    Purpose: We investigated the distribution of cannabinoid receptor subtypes 1 and 2 in the detrusor of different species and studied the effects of cannabinoid receptor 1 and 2 agonists on bladder function.

    Materials and Methods: Cannabinoid receptor 1 and 2 expression was studied with Western blot and immunohistochemistry in rat, monkey and human detrusors. Co-staining was done for markers of sensory nerves using calcitonin gene-related peptide (Euro-Diagnostica, Malmo, Sweden) and transient receptor potential vanilloid 1, and for cholinergic nerves using VAChT (Santa Cruz Biotechnology, Santa Cruz, California). Actions of the endogenous cannabinoid receptor-1 and 2 agonist anandamide (Sigma (R)), and the cannabinoid receptor 1 and 2 agonist CP55,940 (Sigma) on isolated detrusor and during cystometry in conscious rats were recorded.

    Results: Higher expression of cannabinoid receptor 2 but not cannabinoid receptor 1 was noted in the mucosa than in the detrusor. Compared to the detrusor larger amounts of cannabinoid receptor 2 containing nerves that also expressed transient receptor potential vanilloid 1 or calcitonin gene-related peptide were observed in the suburothelium. Nerve fibers containing cannabinoid receptor 2 and VAChT were located in the detrusor. Neither anandamide nor CP55,940 affected isolated detrusor carbachol (Sigma) contractions. Nerve contractions were enhanced by 10 mu M anandamide and decreased by 10 AM CP55,940 (P&lt;0.05). In vivo CP55,940 increased the micturition interval by 46% and threshold pressure by 124% (p &lt;0.05). Anandamide increased threshold pressure by 26% and decreased the micturition interval by 19% (p &lt;0.05 and &lt;0.01, respectively).

    Conclusions: The distribution of cannabinoid receptor 2 on sensory nerves and in the urothelium, and effects by CP55940 on the micturition interval and threshold pressure suggest a role for cannabinoid receptor 2 in bladder afferent signals. Co-expression of VAChT and cannabinoid receptor 2, and effects by CP55940 on nerve contractions suggest a cannabinoid receptor 2 mediated modulatory effect on cholinergic nerve activity. Anandamide may not be a good tool for cannabinoid receptor studies due to its activity at other receptors.

  • 38.
    Gratzke, Christian
    et al.
    University Lund Hospital.
    Streng, Tomi
    University Turku.
    Stief, Christian G
    University Munich.
    Alroy, Iris
    Pharmos Ltd, Rehovot, Israel .
    Limberg, Brian J
    Procter and Gamble Co.
    Downs, Thomas R
    Procter and Gamble Co.
    Rosenbaum, Jan S
    Procter and Gamble Co.
    Hedlund, Petter
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Karl-Erik
    Wake Forest Institute Regenerat Med.
    Cannabinor, a Selective Cannabinoid-2 Receptor Agonist, Improves Bladder Emptying in Rats With Partial Urethral Obstruction2011In: JOURNAL OF UROLOGY, ISSN 0022-5347, Vol. 185, no 2, p. 731-736Article in journal (Refereed)
    Abstract [en]

    Purpose: We studied the effects of chronic treatment with the novel selective cannabinoid 2 receptor agonist cannabinor (Procter andamp; Gamble Pharmaceuticals, Cincinnatti, Ohio) on bladder function in conscious rats with partial urethral obstruction and on the functional properties of isolated detrusor muscle. Materials and Methods: A total of 24 female Sprague-Dawley(R) rats with surgically created partial urethral obstruction received daily intraperitoneal injections of 3 mg/kg cannabinor (12) or saline as controls (12) for 2 weeks. Cystometry was done, the rats were sacrificed and the bladders were prepared for in vitro studies. Results: Mean +/- SEM bladder weight was 0.97 +/- 0.15 gm in controls and 0.53 +/- 0.08 gm in cannabinor treated rats (p andlt; 0.05). There was no difference between the groups in the mean micturition interval, or mean baseline, threshold, flow or maximum pressure. In controls and cannabinor treated rats mean post-void residual volume was 0.28 +/- 0.07 and 0.06 +/- 0.02 ml, mean micturition compliance was 0.032 +/- 0.006 and 0.069 +/- 0.016 ml/cm H2O, and mean bladder wall force at the start of flow was 950 +/- 280 and 1,647 +/- 325 mN/gm, respectively (each p andlt; 0.05). Nonvoiding contractions were significantly less frequent in cannabinor treated rats than in controls. We noted no difference in carbachol (Sigma(R)) half maximum concentration between the groups but the carbachol maximum response in detrusor strips from cannabinor treated rats was significantly higher than that in control strips. Conclusions: In rats with partial urethral obstruction treated daily for 14 days with cannabinor bladder weight was lower, the ability to empty the bladder was preserved and nonvoiding contraction frequency was low compared to those in controls. Detrusor preparations from cannabinor treated rats showed a higher response to nerve stimulation than those from controls. Selective cannabinoid 2 receptor activation may be a novel principle to enable improved bladder function after partial urethral obstruction.

  • 39.
    Gratzke, Christian
    et al.
    Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
    Streng, Tomi
    Department of Pharmacology, Turku University, Turku, Finland.
    Stief, Christian G.
    Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
    Downs, Thomas R.
    Women's Health, Procter & Gamble Health Care, Cincinnati, OH, USA.
    Alroy, Iris
    Pharmos Limited, Rehovot, Israel.
    Rosenbaum, Jan S
    Women's Health, Procter & Gamble Health Care, Cincinnati, OH, USA.
    Andersson, Karl-Erik
    Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA.
    Hedlund, Petter
    Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden.
    Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 57, no 6, p. 1093-1100Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cannabinoid (CB) receptors may be involved in the control of bladder function; the role of CB receptor subtypes in micturition has not been established.

    OBJECTIVES: Our aim was to evaluate the effects of cannabinor, a novel CB2 receptor agonist, on rat bladder function.

    DESIGN, SETTING, AND PARTICIPANTS: Sprague Dawley rats were used. Distribution of CB2 receptors in sensory and cholinergic nerves of the detrusor was studied. Selectivity of cannabinor for human and rat CB receptors was evaluated. Effects of cannabinor on rat detrusor and micturition were investigated.

    MEASUREMENTS: Immunohistochemistry, radioligand binding, tritium outflow assays, organ bath studies of isolated bladder tissue, and cystometry in awake rats were used.

    RESULTS AND LIMITATIONS: CB2 receptor immunoreactivity was expressed in the urothelium and in sensory and cholinergic bladder nerves. Cannabinor exhibited similar binding at human and rat CB2 receptors and a 321-fold functional selectivity for the CB2 receptor versus the CB1 receptor. Cannabinor had no effect on isolated detrusor muscle function. In vivo, cannabinor 3.0mg/kg increased micturition intervals and volumes by 52% (p<0.05) and 96% (p<0.01), respectively, and increased threshold and flow pressures by 73% (p<0.01) and 49% (p<0.001), respectively. Cannabinor 0.3 or 1.0mg/kg or vehicle did not affect urodynamic parameters.

    CONCLUSIONS: Considering that CB2 receptors are localized on sensory nerves and on the urothelium and that cannabinor had effects on "afferent" urodynamic parameters, peripheral CB2 receptors may be involved in sensory functions of rat micturition. Effects of cannabinor on cholinergic nerve activity in normal bladder tissue appear to be limited.

  • 40.
    Gratzke, Christian
    et al.
    Lund University Hospital.
    Streng, Tomi
    Lund University Hospital.
    Waldkirch, Eginhard
    Hannover Medical School.
    Sigl, Katja
    Ludwig Maximilians University Hospital.
    Stief, Christian
    Ludwig Maximilians University Hospital.
    Andersson, Karl-Erik
    Wake Forest University.
    Hedlund , Petter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Transient Receptor Potential A1 (TRPA1) Activity in the Human Urethra-Evidence for a Functional Role for TRPA1 in the Outflow Region2009In: EUROPEAN UROLOGY, ISSN 0302-2838 , Vol. 55, no 3, p. 696-704Article in journal (Refereed)
    Abstract [en]

    Background: A role for the transient receptor potential (TRP) A1 ion channel in rat lower urinary tract (LUT) sensation and disease has been proposed, but in the human LUT no information on TRPA1 activity is available.

    Objectives: To investigate the distribution of TRPA1 in the human urethra and to study the effect of TRPA1 agonists on isolated urethral strip preparations.

    Design, settings, and participants: Urethral specimens were obtained preoperatively from 10 patients and were freshly prepared for Western blot, immunohistochemistry, and functional in vitro investigations.

    Measurements: The expression patterns of TRPA1 were studied with Western blot and immunohistochemistry. The effects of allyl isothiocyanate (A1), cinnamaldehyde (CA), and NaHS (donor of H2S) on tension of urethral strips were investigated in tissue baths.

    Results and limitations: TRPA1 immunoreactivity (-IR) was found in nerve fibres in the suburothelial space and was also located to nerve fibres of the muscle layer. Single TRPA1-IR nerves extended into the urothelium. A majority, but not all TRPA1-IR nerves also expressed immunoreactivity for CGRP or TRPV1. In the urothelium, TRPV1 was located to the outer layers whereas TRPA1 was observed in basal urothelial cells. Interspersed between strands of smooth muscle cells of the urethral wall, TRPA1- and vimentin-IR cells containing central nuclei and slender cytoplasmatic extensions were observed. In functional experiments, TRPA1-agonists had no contractile effect in urethral preparations. After precontraction with phenylephrine, AI, CA, and NaHS caused concentration-dependent relaxations of urethral strip preparations.´

    Conclusions: The localization of TRPA1 to nerves that also express TRPV1 and CGRP, and in urothelial cells and interstitial cells, as well as the findings that TRPA1 agonists can modify tone of urethral preparations, propose a role for TRPA1 in afferent and efferent sensory signaling of the human outflow region.

  • 41.
    Gratzke, Christian
    et al.
    Wake Forest Institute Regenerat Med.
    Weinhold, Philipp
    University of Munich.
    Reich, Oliver
    University of Munich.
    Seitz, Michael
    University of Munich.
    Schlenker, Boris
    University of Munich.
    Stief, Christian G
    University of Munich.
    Andersson, Karl-Erik
    Wake Forest Institute Regenerat Med.
    Hedlund, Petter
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Transient Receptor Potential A1 and Cannabinoid Receptor Activity in Human Normal and Hyperplastic Prostate: Relation to Nerves and Interstitial Cells2010In: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 57, no 5, p. 902-910Article in journal (Refereed)
    Abstract [en]

    Background: Ion channel transient receptor potential A1 (TRPA1) and cannabinoid (CB) receptors are involved in mechanoafferent signaling from the bladder and the urethra. Objective: To characterize TRPA1-, CB1-, and CB2-receptor activities in the human prostate. Design, setting, and participants: Prostate specimens were obtained from 12 patients undergoing radical prostatectomy. We studied expressions (n = 6) of TRPA1, CB1, and CB2 receptors and effects of the TRPA1 agonists allyl isothiocyanate (AI), cinnamaldehyde (CA), sodium hydrogen sulfide (NaHS), and CP 55940 (a CB1/CB2 agonist) on prostatic preparations. Measurements: Western blot, immunohistochemistry, and functional experiments were performed. Results and limitations: Western blot detected expected bands for CB1, CB2, and TRPA1. TRPA1 immunoreactivity was located on nerves that were positive for CB1, CB2, calcitonin gene-related peptide (CGRP), nitric oxide synthase (NOS), or vesicular acetylcholine transporter (VAChT). CB1 and CB2 immunoreactivity was found on nerves that were positive for NOS, VAChT, or CGRP. Adrenergic nerves were not immunoreactive for TRPA1, CB1, or CB2. In nodular hyperplasia, nerves containing the above markers were scarce or absent. TRPA1 immunoreactivity was detected in cyclic guanosinemonophosphate-positive basal cells of the glandular epithelium. Basal or subepithelial TRPA1-immunoreactive cells contained vimentin and c-kit immunoreactivity. CA and NaHS relaxed precontracted preparations by 55 +/- 7% and 35 +/- 3% (n = 6 for each). CP 55940, NaHS, AI, capsaicin, and CA decreased nerve contractions up to 27%, 80%, 47%, and 87%, respectively (n = 6 for each). Conclusions: The distribution and function of TRPA1 and CB receptors in prostatic tissue suggest a role for these receptors in mechanoafferent signals, epithelial homeostasis, emission, or inflammation of the human prostate.

  • 42.
    Hannan, Johanna L.
    et al.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Albersen, Maarten
    Urological Research Institute, San Raffaele Hospital, Vita-Salute University, Milan, Italy.
    Kutlu, Omer
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Gratzke, Christian
    Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
    Stief, Christian G.
    Department of Urology, Ludwig-Maximilians-University, Munich, Germany.
    Burnett, Arthur L.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Lysiak, Jeffrey J.
    Department of Urology, University of Virginia, Charlottesville, Virginia, USA.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Bivalacqua, Trinity J.
    The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
    Inhibition of Rho-Kinase Improves Erectile Function, Increases Nitric Oxide Signaling and Decreases Penile Apoptosis in a Rat Model of Cavernous Nerve Injury2013In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 189, no 3, p. 1155-1161Article in journal (Refereed)
    Abstract [en]

    Purpose: Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury.Materials and Methods: Sprague-Dawley(R) rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test.Results: While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls.Conclusions: These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis.

  • 43.
    Hannan, Johanna L.
    et al.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Kutlu, Omer
    Karadeniz Technical University, Trabzon, Turkey.
    Stopak, Bernard L.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Liu, Xiaopu
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Castiglione, Fabio
    San Raffaele Research Institute, Milan, Italy .
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology. San Raffaele Research Institute, Milan, Italy .
    Burnett, Arthur L.
    Johns Hopkins School Med, MD 21287 USA .
    Bivalacqua, Trinity J.
    Johns Hopkins School of Medicine, Baltimore, MD, USA.
    Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats2014In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 11, no 6, p. 1442-1451Article in journal (Refereed)
    Abstract [en]

    Introduction Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods Five groups of rats (8-10 weeks, n=10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-1 (TGF-1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (-SMA) antibodies. Main Outcome Measures We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-1 protein expression; penile fibrosis; penile -SMA content. Results There was a voltage-dependent decline (Pless than0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (Pless than0.05) 14 days after BCNI. There was a slight increase in TGF-1 protein expression after BCNI. Histological analysis showed increased (Pless than0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (Pless than0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile -SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (Pless than0.05). Conclusion HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.

  • 44.
    Hedlund, H.
    et al.
    Institute of Surgery, Bergen University, Norway.
    Hedlund, Petter
    Lund University Hospital.
    Pharmacotherapy in erectile dysfunction agents for self-injection programs and alternative application models1996In: Scandinavian Journal of Urology and Nephrology, Supplementum, ISSN 0300-8886, E-ISSN 1651-2537, Vol. 179, p. 129-38Article, review/survey (Refereed)
    Abstract [en]

    Previously, men with erectile dysfunction (ED) were frequently treated with penile prosthesis implants or considered to have psychogenic impotence. Since the reports by Virag and Brindley in 1932 and 1983, pharmacotherapy, by self-injection programs has become a new therapeutic concept for impotent men. In clinical practice, this application model has been generally accepted as the "golden standard" in the treatment of ED. Papaverine was first used as monotherapy, but because of side-effects such as prolonged erection, priapism, and fibrosis of the corpus cavernosum, single use of the drug was abandoned. Instead, papaverine was introduced in mixtures, e.g. together with alpha adrenoceptor-blockers as phentolamine, and/or prostaglandin E1 (PGE1) in these "cocktails", the dose of papaverine is reduced to 10-15 mg compared to the high doses (80-120 mg) that were used initially. By having two or more drugs in the mixture, a facilitating cascade effect as probably obtained. PGE1 is the only drug that has been approved by the FDA and is today registered in more than 50 countries. Other combination therapies such as vasoactive intestinal polypeptide+ phentolamine, or calcitonin gene-related peptide+ PGE1, have been suggested as suitable alternatives for intracavernosal injection. Transdermal and intraurethral application models may be considered in selected patients. Recently, oral administration of a phosphodiesterase inhibitor (UK-92.480) was reported to improve penile erection in patients with psychogenic impotence. Further clinical results from controlled trials will probably explain if this new oral drug will compete with PGE1 or other agents in self-injection programs.

  • 45.
    Hedlund, H
    et al.
    Nationall Hospital of Norway.
    Hedlund, Petter
    Lund University Hospital.
    Treatment of benign prostatic enlargement with alpha-blockers: an updated review1999In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 33, no 203, p. 9-13Article in journal (Refereed)
    Abstract [en]

    n/a

  • 46.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Cannabinoids and the Endocannabinoid System in Lower Urinary Tract Function and Dysfunction2014In: Neurourology and Urodynamics, ISSN 0733-2467, E-ISSN 1520-6777, Vol. 33, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    AimsTo review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. MethodsReview of MEDLINE using defined search terms, and manual analysis. Articles published in English were included. Results and DiscussionComponents of the endocannabinoid systemcannabinoid (CB) receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amideshave been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues. ConclusionsEvidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.

  • 47.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Editorial Comment on Characteristics of Spontaneous Activity in the Bladder Trigone: in EUROPEAN UROLOGY, vol 56, issue 2, pg 354.2009In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 56, no 2, p. 354-354Article in journal (Other academic)
    Abstract [en]

    n/a

  • 48.
    Hedlund, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. IRCCS Osped San Raffaele, Italy.
    Editorial Material: Everyday Cold Exposure and Urgency in Translation in EUROPEAN UROLOGY2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 68, no 4, p. 662-663Article in journal (Other academic)
    Abstract [en]

    n/a

  • 49.
    Hedlund, Petter
    Lund University Hospital.
    Genes and erectile function2003In: Current Opinion in Urology, ISSN 0963-0643, E-ISSN 1473-6586, Vol. 13, no 5, p. 397-403Article, review/survey (Refereed)
  • 50.
    Hedlund, Petter
    Lund University Hospital.
    Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract-is there a basis for pharmacological targeting of cGMP?2005In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 23, no 6, p. 362-367Article in journal (Refereed)
    Abstract [en]

    Treatment with alpha-adrenoceptor antagonists that reduce the tone of prostatic stromal and urethral smooth muscle has beneficial effects in patients with benign prostatic hyperplasia (BPH) and lower urinary tracts symptoms (LUTS) and has brought attention to regulatory mechanisms of smooth muscle contractility of the outflow region. The prostate, urethra and bladder neck are densely supplied by nitric oxide (NO)-synthase-containing nerves that cause relaxation upon activation. In various experimental models, altered function or activity of the NO/cGMP pathway of the bladder neck and urethra may be related to inappropriate or un-coordinated functions of the bladder outlet and detrusor, but causal connections between alterations in this signaling system, a dysfunctional bladder outlet, and the development of LUTS are not established for humans. The present review focuses on regulatory functions of smooth muscle contractility by the NO/cGMP-pathway in the bladder neck, urethra, and prostate. Disease-related alterations in the NO/cGMP-pathway, and putative options for pharmacological modification of this signaling pathway in the out-flow region are briefly discussed.

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