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  • 1.
    Adner, Mikael
    et al.
    Malmö University Hospital, Sweden.
    Rose, Andrew C
    Johnson and Johnson Pharmaceutical Research and Development, La Jolla, California, USA.
    Zhang, Yaping
    Malmö University Hospital, Sweden.
    Swärd, Karl
    Lund University, Sweden.
    Benson, Mikael
    Malmö University Hospital, Sweden.
    Uddman, Rolf
    Malmö University Hospital, Sweden.
    Shankley, Nigel P
    Johnson and Johnson Pharmaceutical Research and Development, La Jolla, California, USA.
    Cardell, Lars-Olaf
    Malmö University Hospital, Sweden.
    An assay to evaluate the long-term effects of inflammatory mediators on murine airway smooth muscle: evidence that TNFalpha up-regulates 5-HT(2A)-mediated contraction2002In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 137, no 7, p. 971-982Article in journal (Refereed)
    Abstract [en]

    1. Asthma research is arguably limited by an absence of appropriate animal models to study the pharmacology of inflammatory mediators that affect airway hyperresponsiveness and remodelling. Here we assessed an assay based on mouse tracheal segments cultured for 1-32 days, and investigated contractile responses mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long-term exposure to tumour necrosis factor-alpha (TNFalpha). 2. Following culture, in the absence of TNFalpha, maximum contractile responses to KCl and carbachol were similar, with an increase in response up to day two and a decrease to a stable level after 8 days. Maximal relaxations to isoprenaline were not affected by the culture procedure. The potency of KCl and isoprenaline increased throughout the study. DNA microarray data revealed that global gene expression changes were greater when tissues were introduced to culture than when they were maintained in culture. The morphology of smooth muscle cells was maintained throughout the culture period. 3. 5-HT induced a weak contraction in both fresh and cultured (up to 8 days) segments. Culture with TNFalpha produced a time- and concentration-dependent increase in the maximal contraction to 5-HT, evidently mediated by 5-HT(2A) receptors, whereas, the potency for carbachol was reduced. 4. In conclusion, the phenotype of airway smooth muscle remained largely intact during the culture period, even though minor changes were obtained during the first days of culture. The time-dependent effect of TNFalpha indicates the importance of studying the long-term effect of cytokines on the smooth muscle cells in relation to airway hyperresponsiveness and remodelling.

  • 2.
    Hedlund, Petter
    et al.
    University of Lund.
    Alm, P
    University of Lund.
    Andersson, KE
    University of Lund.
    NO synthase in cholinergic nerves and NO-induced relaxation in the rat isolated corpus cavernosum1999In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 127, no 2, p. 349-360Article in journal (Refereed)
    Abstract [sv]
    • In the rat corpus cavernosum (CC), the distribution of immunoreactivity for neuronal and endothelial NO synthase (nNOS and eNOS), and the pattern of NOS-immunoreactive (-IR) nerves in relation to some other nerve populations, were investigated. Cholinergic nerves were specifically immunolabelled with antibodies to the vesicular acetylcholine transporter protein (VAChT).
    • In the smooth muscle septa surrounding the cavernous spaces, and around the central and helicine arteries, the numbers of PGP- and tyrosine hydroxylase (TH)-IR terminals were large, whereas neuropeptide Y (NPY)-, VAChT-, nNOS-, and vasoactive intestinal polypeptide (VIP)-IR terminals were found in few to moderate numbers.
    • Double immunolabelling revealed that VAChT- and nNOS-IR terminals, VAChT- and VIP-IR terminals, nNOS-IR and VIP-IR terminals, and TH- and NPY-IR terminals showed coinciding profiles, and co-existence was verified by confocal laser scanning microscopy. TH immunoreactivity was not found in VAChT-, nNOS-, or VIP-IR nerve fibres or terminals.
    • An isolated strip preparation of the rat CC was developed, and characterized. In this preparation, cumulative addition of NO to noradrenaline (NA)-contracted strips, produced concentration-dependent, rapid, and almost complete relaxations. Electrical field stimulation of endothelin-1-contracted preparations produced frequency-dependent responses: a contractile twitch followed by a fast relaxant response. After cessation of stimulation, there was a slow relaxant phase. Inhibition of NO synthesis, or blockade of guanylate cyclase, abolished the first relaxant phase, whereas the second relaxation was unaffected.
    • The results suggest that in the rat CC, nNOS, VAChT-, and VIP-immunoreactivities can be found in the same parasympathetic cholinergic neurons. Inhibitory neurotransmission involves activation of the NO-system, and the release of other, as yet unknown, transmitters.
  • 3.
    Hedlund, Petter
    et al.
    Lund University Hospital.
    Alm, P.
    Lund University Hospital.
    Ekström, P.
    Lund University Hospital.
    Fahrenkrug, J.
    Bispebjerg Hospital, University of Copenhagen.
    Hannibal, J.
    Bispebjerg Hospital, University of Copenhagen.
    Hedlund, H.
    Lund University Hospital.
    Larsson, B.
    Lund University Hospital.
    Andersson, K. E.
    Lund University Hospital.
    Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum1995In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 116, no 4, p. 2258-2266Article in journal (Refereed)
    Abstract [en]

    1. The distribution and effects of pituitary adenylate cyclase-activating polypeptide (PACAP-27 and -38), helospectin (Hel-1 and Hel-2), and vasoactive intestinal polypeptide (VIP), were investigated in isolated preparations of human corpus cavernosum (CC). 2. Immunohistochemistry revealed coinciding profiles of nerve structures that showed immunoreactivities for VIP and PACAP, and VIP and Hel. Confocal microscopy showed the co-existence of VIP- and PACAP-immunoreactivities, and VIP- and Hel-immunoreactivities in most (90%) varicose nerve structures. 3. As determined by radioimmunoassay, the amounts of VIP, PACAP-27, and PACAP-38 in the preparations were 61.7 +/- 11.6, 0.1 +/- 0.05, and 3.7 +/- 0.5 pmol g-1 wet weight of tissue (pmol g-1 wet wt.), respectively. In tissue from patients with diabetes, the content of VIP was lower (13.7 +/- 0.5 pmol g-1 wet wt.), whereas that of PACAP (-27 and -38) was unchanged. 4. Cyclic nucleotide levels were determined in preparations exposed to PACAP-27, PACAP-38, Hel-1, Hel-2, and VIP. All the peptides, but Hel-2, significantly increased the concentrations of cyclic AMP, whereas the levels of cyclic GMP were unchanged. 5. The peptides concentration-dependently relaxed noradrenaline-contracted preparations. The order of potency was VIP > PACAP 27 > Hel-1 > Hel-2 > PACAP-38. 6. Hel-1, VIP and PACAP-27 effectively counteracted electrically induced contractions. At 10(-6) M, the highest peptide concentration used, the inhibitory effects obtained reached 96 +/- 3%, 87 +/- 6%, and 80 +/- 3%, respectively. 7. The results suggest that PACAP and Hel-1 are co-localized with VIP in nerve structures within the human cavernous tissue, and that the peptides are effective relaxants of CC preparations in vitro. The role of the investigated peptides for penile erection remains to be established.

  • 4. Hutcheson, I-R
    et al.
    Grifith, T-M
    Pitman, M R
    Towart, R
    Gregersen, M R
    Refsum, H
    Karlsson, J
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Iodinated radiographic contrast media inhibit shear stress- and agonist-evoked release of No by the endothelium.1999In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 128, p. 451-457Article in journal (Refereed)
  • 5.
    Kirchberger, Tanja
    et al.
    University Medical Centre Hamburg-Eppendorf, Germany..
    Wagner, G
    University of Bath, UK.
    Xu, Jianfeng
    Peking University, Beijing, China.
    Cordiglieri, C
    Max-Planck-Institute for Neurobiology, Martinsried, Germany.
    Wang, P.
    Peking University, Beijing, China.
    Gasser, Andreas
    University Medical Centre Hamburg-Eppendorf, Germany..
    Fliegert, Ralf
    University Medical Centre Hamburg-Eppendorf, Germany..
    Bruhn, Sören
    University Medical Centre Hamburg-Eppendorf, Germany..
    Flügel, Andreas
    Max-Planck-Institute for Neurobiology, Martinsried, Germany.
    Lund, Fren
    Trudeau Institute, Saranac Lake, NY, USA.
    Zhang, Lee
    Peking University, Beijing, China.
    Potter, Barry
    University of Bath, UK.
    Guse, Andreas
    University Medical Centre Hamburg-Eppendorf, Germany..
    Cellular effects and metabolic stability of N1-cyclicinosinediphosphoribose and its derivatives2006In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 149, no 4Article in journal (Refereed)
    Abstract [en]

    Background and purpose:

    Recently, a number of mimics of the second messenger cyclic ADP-ribose (cADPR) with replacement of adenosine by inosine were introduced. In addition, various alterations in the molecule ranging from substitutions at C8 of the base up to full replacement of the ribose moieties still retained biological activity. However, nothing is known about the metabolic stability and cellular effects of these novel analogues.

    Experimental approach:

    cADPR and the inosine-based analogues were incubated with CD38, ADP-ribosyl cyclase and NAD-glycohydrolase and metabolism was analysed by RP-HPLC. Furthermore, the effect of the analogues on cytokine expression and proliferation was investigated in primary T-lymphocytes and T-lymphoma cells.

    Key results:

    Incubation of cADPR with CD38 resulted in degradation to adenosine diphosphoribose. ADP-ribosyl cyclase weakly catabolised cADPR whereas NAD-glycohydrolase showed no such activity. In contrast, N1-cyclic inosine 5′-diphosphoribose (N1-cIDPR) was not hydrolyzed by CD38. Three additional N1-cIDPR analogues showed a similar stability. Proliferation of Jurkat T-lymphoma cells was inhibited by N1-cIDPR, N1-[(phosphoryl-O-ethoxy)-methyl]-N9-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthine-cyclic pyrophosphate (N1-cIDP-DE) and N1-ethoxymethyl-cIDPR (N1-cIDPRE). In contrast, in primary T cells neither proliferation nor cytokine expression was affected by these compounds.

    Conclusions and Implications:

    The metabolic stability of N1-cIDPR and its analogues provides an advantage for the development of novel pharmaceutical compounds interfering with cADPR mediated Ca2+ signalling pathways. The differential effects of N1-cIDPR and N1-cIDPRE on proliferation and cytokine expression in primary T cells versus T-lymphoma cells may constitute a starting point for novel anti-tumor drugs.

  • 6.
    Kugelberg, Fredrik
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry.
    Apelqvist, Gustav
    Department of Clinical Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
    Carlsson, Björn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, no 8, p. 1683-1690Article in journal (Refereed)
    Abstract [en]
    • The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted.

    • By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed.

    • In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg−1 day−1 were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions.

    • In the group treated with 100 mg kg−1 day−1, the serum and brain total CIT levels were found to be 20 times and 6 – 8 times higher than in the rats treated with 10 or 20 mg kg−1 day−1, respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum.

    • In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed.

    • In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

  • 7. Lördal, Mikael
    et al.
    Navalesi, Giovanni
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Maggi, Carlo A
    Hellström, Per M
    A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 134, no 1, p. 215-223Article in journal (Refereed)
    Abstract [en]

    1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg-1 min-1 intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

  • 8.
    Matsumoto, K
    et al.
    Lund University Hospital.
    Yoshida, M
    Kumamoto University School of Medicine.
    Andersson, KE
    Lund University Hospital.
    Hedlund, Petter
    Lund University Hospital.
    Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum2005In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 146, no 2, p. 259-267Article in journal (Refereed)
    Abstract [en]

    The study was performed to clarify if apomorphine at the level of the rat corpus cavernosum can produce erectile responses or interfere with nerve-induced penile erection. Apomorphine (10(-9)-10(-4) M) exhibited a 10-fold higher potency to relax phenylephrine (Phe)- than endothelin-1 (ET-1)-induced contractions. Relaxant effects of apomorphine in Phe-activated corpus cavernosum did not change tissue levels of cyclic nucleotides, and were unaffected by inhibition of the synthesis of nitric oxide, or by inhibition of the soluble guanylate cyclase. Relaxations by apomorphine of ET-1-contracted rat corpus cavernosum were not influenced by alpha2-adrenoceptor blockade (yohimbine, 10(-7) M), or by the dopamine D1-like receptor antagonist SCH 23390 (10(-6) M). Clozapine (10(-6) M), a proposed dopamine D2-like receptor antagonist, partly reduced apomorphine-induced relaxations, and significantly altered the -log IC50 value for apomorphine. Nerve-induced contractions of the rat corpus cavernosum were attenuated by apomorphine in a concentration-dependent and biphasic manner. Yohimbine (10(-7) M) abolished the biphasic concentration-response pattern. SCH 23390 (10(-6) M) attenuated the inhibitory effects of apomorphine on contractions, and significantly altered the -log IC50 value for the compound. In anesthetized rats (50 mg kg(-1) pentobarbital sodium, 10 mg kg(-1) ketamine), intracavernous apomorphine (100, 300, or 1000 nmol) did not have effects on basal cavernous pressure under resting conditions, and did not affect filling or emptying rates, or peak pressures of the rat corpus cavernosum during submaximal activation of the cavernous nerve. In awake rats, apomorphine produced a maximal number of erections at 300 nmol kg(-1). In the rat isolated corpus cavernosum, pre- and postjunctional effects of apomorphine appear to involve dopamine D1- and D2-like receptors, as well as alpha-adrenoceptors. At relevant systemic doses of apomorphine, peripheral effects of the compound are unlikely to contribute to its proerectile effects in rats.

  • 9.
    Mizusawa, Hiroya
    et al.
    Department of Clinical Pharmacology, University of Lund, Sweden.
    Hedlund, Petter
    Department of Clinical Pharmacology, University of Lund, Sweden.
    Håkansson, Anders
    Department of Microbiology, Immunology and Glycobiology, University of Lund, Sweden.
    Alm, Per
    Department of Pathology, University of Lund, Sweden.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, University of Lund, Sweden.
    Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum.2001In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 132, no 6, p. 1333-1341Article in journal (Refereed)
    Abstract [en]

    1. In normal mice, the distribution of adrenergic, cholinergic, some peptidergic, and neuronal nitric oxide synthase (nNOS)-containing nerves were investigated. Functional in vitro correlates were obtained. An in vivo model was developed in which erectile haemodynamics in response to drugs or nerve-stimulation were studied. 2. Immunoreactivities for vesicular acetylcholine transporter protein (VAChT), nNOS-, and vasoactive intestinal polypeptide (VIP), co-existed in nerve fibres and terminal varicosities. Immunoreactivities for neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were found in the same nerve structures. 3. Chemical sympathectomy abolished TH- and NPY-IR nerve structures in cavernous smooth muscle bundles. The distribution of calcitonin gene-related peptide (CGRP)-, nNOS-, VAChT- and VIP-IR nerve structures was unchanged. 4. In endothelial cells of the central and helicine arteries, veins and venules, intense immunoreactivity for endothelial NOS (eNOS) was observed. No distinct eNOS-IR cells were found lining the cavernous sinusoids. 5. In vitro, nerve-induced relaxations were verified, and endothelial NO/cyclic GMP-mediated relaxant responses were established. VIP and CGRP had small relaxant effects. A functioning adenylate cyclase/cyclic AMP pathway was confirmed. 6. Neuronal excitatory responses were abolished by prazosin, or forskolin. VIP and CGRP counteracted contractions, whereas NPY and scopolamine enhanced excitatory responses. 7. In vivo, erectile responses were significantly attenuated by L-NAME (50 mg kg(-1)) and facilitated by sildenafil (200 microg kg(-1)). 8. It is concluded that the mouse is a suitable model for studies of erectile mechanisms in vitro and in vivo.

  • 10.
    Mizusawa, Hiroya
    et al.
    Department of Clinical Pharmacology, University of Lund, Sweden..
    Hedlund, Petter
    Department of Clinical Pharmacology, University of Lund, Sweden.
    Sjunnesson, Johan
    Department of Clinical Pharmacology, University of Lund, Sweden..
    Brioni, Jorge D
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories.
    Sullivan, James P
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories.
    Andersson, Karl-Erik
    Department of Clinical Pharmacology, University of Lund, Sweden..
    Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist.2002In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 136, no 5, p. 701-8Article in journal (Refereed)
    Abstract [en]

    1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.

  • 11.
    Mostafa Elbadawy, Hossein
    et al.
    Taibah University, Saudi Arabia; Veneto Eye Bank Fdn, Italy.
    Mirabelli, Pierfrancesco
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Xeroudaki, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Parekh, Mohit
    Veneto Eye Bank Fdn, Italy.
    Bertolin, Marina
    Veneto Eye Bank Fdn, Italy.
    Breda, Claudia
    Veneto Eye Bank Fdn, Italy.
    Cagini, Carlo
    University of Perugia, Italy.
    Ponzin, Diego
    Veneto Eye Bank Fdn, Italy.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Ferrari, Stefano
    Veneto Eye Bank Fdn, Italy.
    Effect of connexin 43 inhibition by the mimetic peptide Gap27 on corneal wound healing, inflammation and neovascularization2016In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 173, no 19, p. 2880-2893Article in journal (Refereed)
    Abstract [en]

    Background and PurposeThe connexin 43 (Cx43) mimetic peptide Gap27 was designed to transiently block the function of this gap junction. This study was undertaken to investigate the effect of Gap27 on corneal healing, inflammation and neovascularization. Experimental ApproachThe effect of Gap27 on wound healing, inflammation and vascularization was assessed in primary human corneal epithelial cells (HCEC) in vitro and whole human corneas ex vivo, and in an in vivo rat wound healing model. Key ResultsGap27 enhanced the wound closure of HCEC in vitro and accelerated wound closure and stratification of epithelium in human corneas ex vivo, but did not suppress the corneal release of inflammatory mediators IL-6 or TNF- in vivo. In human corneas ex vivo, F4/80 positive macrophages were observed around the wound site. In vivo, topical Gap27 treatment enhanced the speed and density of early granulocyte infiltration into rat corneas. After 7days, the expressions of TNF- and TGF1 were elevated and correlated with inflammatory cell accumulation in the tissue. Additionally, Gap27 did not suppress VEGF release in organotypic culture, nor did it suppress early or late VEGFA expression or neovascularization in vivo. Conclusions and ImplicationsGap27 can be effective in promoting the healing of superficial epithelial wounds, but in deep stromal wounds it has the potential to promote inflammatory cell migration and accumulation in the tissue and does not suppress the subsequent neovascularization response. These results support the proposal that Gap27 acts as a healing agent in the transient, early stages of corneal epithelial wounding.

  • 12.
    Ny, L
    et al.
    Lund University Hospital.
    Pfeifer, A
    Salk Institute.
    Aszodi, A
    Lund University Hospital.
    Ahmad, M
    Lund University Hospital.
    Alm, P
    Lund University Hospital.
    Hedlund, Petter
    Lund University Hospital.
    Fassler, R
    Lund University Hospital.
    Andersson, KE
    Lund University Hospital.
    Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP-dependent protein kinase I2000In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 129, no 2, p. 395-401Article in journal (Refereed)
    Abstract [en]

    1. Guanosine 3', 5'-cyclic monophosphate (cyclic GMP)-dependent kinase I (cGKI) is a major receptor for cyclic GMP in a variety of cells. Mice lacking cGKI exhibit multiple phenotypes, including severe defects in smooth muscle function. We have investigated the NO/cGMP- and vasoactive intestinal polypeptide (VIP)/adenosine 3', 5'-cyclic monophosphate (cyclic AMP)-signalling pathways in the gastric fundus of wild type and cGKI-deficient mice. 2. Using immunohistochemistry, similar staining patterns for NO-synthase, cyclic GMP- and VIP-immunoreactivities were found in wild type and cGKI-deficient mice. 3. In isolated, endothelin-1 (3 nM - 3 microM)-contracted, muscle strips from wild type mice, electrical field stimulation (1 - 16 Hz) caused a biphasic relaxation, one initial rapid, followed by a more slowly developing phase. In preparations from cGKI-deficient mice only the slowly developing relaxation was observed. 4. The responses to the NO donor, SIN-1 (10 nM - 100 microM), and to 8-Br-cyclic GMP (10 nM - 100 microM) were markedly impaired in strips from cGKI-deficient mice, whereas the responses to VIP (0.1 nM - 1 microM) and forskolin (0.1 nM - 1 microM) were similar to those in wild type mice. 5. These results suggest that cGKI plays a central role in the NO/cGMP signalling cascade producing relaxation of mouse gastric fundus smooth muscle. Relaxant agents acting via the cyclic AMP-pathway can exert their effects independently of cGKI.

  • 13.
    Nylander, Sven
    et al.
    Department of Molecular Pharmacology, Preclinical R and D, AstraZeneca R and D, Mölndal, Sweden.
    Mattsson, Christer
    Department of Molecular Pharmacology, Preclinical R and D, AstraZeneca R and D, Mölndal, Sweden.
    Ramström, Sofia
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Synergistic action between inhibition of P2Y12/P2Y1 and P2Y12/thrombin in ADP- and thrombin-induced human platelet activation2004In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 142, no 8, p. 1325-1331Article in journal (Refereed)
    Abstract [en]
    • The objective of this study was to investigate if there is a synergistic effect of a combination of P2Y12 and P2Y1 inhibition and P2Y12 and thrombin inhibition, on ADP- and thrombin-induced platelet activation, respectively. The rationale being that these combinations will cause a concurrent inhibition of both Gαq and Gαi signalling.

    • Blood from healthy volunteers was preincubated with AR-C69931MX, a reversible P2Y12 antagonist; MRS2179, a reversible P2Y1 antagonist; or melagatran, a direct reversible thrombin inhibitor; alone or in various combinations prior to activation with ADP or thrombin. Platelet function in whole blood was assessed by flow cytometry using the antibody PAC-1 to estimate the expression of active αIIbβ3 (the fibrinogen receptor GPIIb/IIIa). A synergistic effect was evaluated by comparing the concentrations in the different combinations with those of corresponding equipotent concentrations of each single inhibitor alone. The equipotent single concentrations were experimentally obtained from concentration response curves performed in parallel.

    • A synergistic effect regarding inhibition of ADP-induced platelet activation (10 μM) was obtained with different combinations of AR-C69931MX and MRS2179.

    • Inhibition of thrombin-induced platelet activation (2 nM) with combinations of AR-C69931MX and the thrombin inhibitor melagatran did also result in a strong synergistic effect.

    • To our knowledge, this is the first time that data supporting a synergistic effect has been published for the inhibitor combinations described.

    • Whether this synergistic effect in vitro also results in an improved antithrombotic effect in vivo with or without an increased risk of bleeding remains to be studied in well-conducted clinical studies.

  • 14. Sayer, Brooke
    et al.
    Lu, Jun
    Green, Christina
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Akhtar, Mahmood
    McKay, Derek M
    Dextran sodium sulphate-induced colitis perturbs muscarinic cholinergic control of colonic epithelial ion transport2002In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 135, p. 1794-1800Article in journal (Refereed)
  • 15.
    Stoen, R
    et al.
    Trondheim, Norge.
    Lossius, K
    Trondheim, Norge.
    Karlsson, JO
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Acetylcholine-induced vasodilation may depend entirely upon NO in the femoral artery of young piglets2003In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 138, no 1, p. 39-46Article in journal (Refereed)
    Abstract [en]

    1. To characterize agonist-induced relaxation in femoral artery rings from young piglets, we compared the effect of a NOS-inhibitor N?-nitro-L-arginine (L-NOARG), an NO-inactivator oxyhaemoglobin (HbO) and a soluble guanyl cyclase(sGC)-inhibitor 1H-[1,2,4]Oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ) on acetylcholine(ACh)-induced relaxation. The involvement of K+ channel activation was studied on relaxations induced by ACh, the two NO donors sodium nitroprusside (SNP) and diethylamine (DEA) NONOate, and the cell membrane permeable guanosine 3'5' cyclic monophosphate (cGMP) analogue 8-Br-cGMP. 2. Full reversal of phenylephrine-mediated precontraction was induced by ACh (1 nM-1 ╡M) (pD2 8.2▒0.01 and Rmax 98.7▒0.3%). L-NOARG (100 ╡M) partly inhibited relaxation (pD2 7.4▒0.02 and Rmax 49.6▒0.8%). The L-NOARG/indomethacin(IM)-resistant response displayed characteristics typical for endothelium-derived hyperpolarizing factor (EDHF), being sensitive to a combination of the K+ channel blockers charybdotoxin (CTX) (0.1 ╡M) and apamin (0.3 ╡M). 3. ODQ (10 ╡M) abolished relaxations induced by ACh and SNP. L-NOARG/IM-resistant relaxations to ACh were abolished by HbO (20 ╡M). 4. Ouabain (1 ╡M) significantly inhibited ACh-induced L-NOARG/IM-resistant relaxations and relaxations induced by SNP (10 ╡M) and 8-Br-cGMP (0.1 mM). A combination of ouabain and Ba2+ (30 ╡M) almost abolished L-NOARG/IM-resistant ACh-induced relaxation (Rmax 7.7▒2.5% vs 23.4▒6.4%, with and without Ba2+, respectively, P<0.05). 5. The present study demonstrates that in femoral artery rings from young piglets, despite an L-NOARG/IM-resistant component sensitive to K+ channel blockade with CTX and apamin, ACh-induced relaxation is abolished by sGC-inhibition or a combination of L-NOARG and HbO. These findings suggest that relaxation can be fully explained by the NO/cGMP pathway.

  • 16.
    Villa, L
    et al.
    Ist Science San Raffaele, Italy .
    Buono, R
    Ist Science San Raffaele, Italy .
    Fossati, N
    Ist Science San Raffaele, Italy .
    Rigatti, P
    University of Vita Salute San Raffaele, Italy .
    Montorsi, F
    Ist Science San Raffaele, Italy .
    Benigni, F
    Ist Science 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 .
    Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters2013In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 169, no 1, p. 230-238Article in journal (Refereed)
    Abstract [en]

    Background and Purpose 1-adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the 1A-AR selective antagonist silodosin (compared to tamsulosin and prazosin) on ureter pressures in a rat model of ureter obstruction, and on contractions of human and rat isolated ureters. Experimental Approach After ethical approval, ureters of male rats were cannulated beneath the kidney pelvis for in vivo ureteral intraluminal recording of autonomous peristaltic pressure waves. A partial ureter obstruction was applied to the distal ureter. Mean arterial blood pressure (MAP) was recorded. Approximate clinical and triple clinical doses of the 1-AR antagonists were given intravenously. Effects by the 1-AR antagonists on isolated human and rat ureters were studied in organ baths. Key Results Intravenous silodosin (0.10.3mgkg1) or prazosin (0.030.1mgkg1) reduced obstruction-induced increases in intraluminal ureter pressures by 2137% or 1840% respectively. Corresponding effects by tamsulosin (0.01 or 0.03mgkg1) were 920%. Silodosin, prazosin and tamsulosin reduced MAP by 1012%, 2526% (P andlt; 0.05), or 1825% (P andlt; 0.05) respectively. When effects by the 1A-AR antagonists on obstruction-induced ureter pressures were expressed as a function of MAP, silodosin had six- to eightfold and 2.5- to eightfold better efficacy than tamsulosin or prazosin respectively. Silodosin effectively reduced contractions of both human and rat isolated ureters. Conclusions and Implications Silodosin inhibits contractions of the rat and human isolated ureters and has excellent functional selectivity in vivo to relieve pressure-load of the rat obstructed ureter. Silodosin as pharmacological ureter stone expulsive therapy should be clinically further explored.

  • 17.
    Zimmerli, Dario
    et al.
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors2017In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 174, no 24, p. 4600-4610Article in journal (Refereed)
    Abstract [en]

    Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signalling and many types of human cancers was established more than a decade ago, no Wnt signalling inhibitors have made it into the clinic so far. One reason for this is that no pathway-specific kinase is known. Additionally, targeting the protein-protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance. Wnt/β-catenin signalling is involved in virtually all aspects of embryonic development and in the control of the homeostasis of adult tissues. Encouragingly, however, in recent years, first successes with Wnt-pathway inhibitors have been reported in mouse models of disease. In this review, we summarize possible roads to follow during the quest to pharmacologically modulate the Wnt signalling pathway in cancer.

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