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  • 1.
    Asplund Persson, Anna
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Peter
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries2005In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 521, no 1-3, p. 124-132Article in journal (Refereed)
    Abstract [en]

    We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3′,5′-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, dephostatin increased the cGMP content and the serine phosphorylation of vasodilator-stimulated phosphoprotein. Dephostatin also inhibited the relaxation induced by acetylcholine and the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP). In contrast, dephostatin did not affect the NO-dependent actions of 1,2,3,4-Oxatriazolium, 3-(3-chloro-2-metylphenyl)-5-[[(4methylphenyl)sulfonyl]amino]-hydroxide inner salt (GEA 3175). Measurement of NO revealed that dephostatin accelerated the consumption of NO. In conclusion, dephostatin exerts dual effects on the NO/cGMP-signalling pathway in iliac arteries. The drug actions included scavenging of NO, but also stimulation of cGMP production. These effects were not related to inhibition of tyrosine phosphatases.

  • 2.
    Asplund Persson, Anna K
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Palmér, Louise
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Peter
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Characterisation of GEA 3175 on human platelets: comparison with S-nitroso-N-acetyl-D,L-penicillamine2004In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 496, no 1-3, p. 1-9Article in journal (Refereed)
    Abstract [en]

    By comparing the effect of two nitric oxide (NO)-containing compounds, we found that S-nitroso-N-acetyl-d,l-penicillamine (SNAP), but not GEA 3175 (1,2,3,4-Oxatriazolium,3-(3-chloro-2-metylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino]-, hydroxide inner salt), released NO. Despite this, both drugs elevated cyclic guanosine 3′,5′-monophosphate (cGMP) levels in human platelets. However, SNAP was more effective after short exposure times (5 and 20 s). The compounds also inhibited thrombin-induced rises in cytosolic Ca2+. Time studies revealed that the action of SNAP rapidly declined by increasing the length of incubation (from 5 s to 30 min). This desensibilisation phenomenon mainly involved the release of Ca2+ from intracellular stores. In comparison, GEA 3175-induced inhibition of cytosolic Ca2+ signalling was much more long-lasting. The soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of GEA 3175 on cytosolic Ca2+. Consequently, this inhibition depends solely on the increase in cGMP. In summary, differences between GEA 3175 and SNAP were observed in NO releasing, cGMP elevating and Ca2+ suppressive properties.

  • 3.
    Asplund Persson, Anna
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Zalavary, Stefan
    Linköping University, Faculty of Health Sciences.
    Lindström, Eva
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per A
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets2005In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 517, no 3, p. 149-157Article in journal (Refereed)
    Abstract [en]

    We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.

    In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.

  • 4.
    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.

  • 5.
    Ghofrani, Saeed
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Joghataei, Mohammad-Taghi
    Cellular and Molecular Research Center and Department of Neuroscience, School of Advanced Technology, Iran University of Medical Sciences, Tehran, Iran.
    Mohseni, Simin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Baluchnejadmojarad, Tourandokht
    Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
    Bagheri, Maryam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Department of Physiology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran.
    Khamse, Safoura
    Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
    Roghani, Mehrdad
    Neurophysiology Research Center, Shahed University, Tehran, Iran.
    Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms2015In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 764, p. 195-201Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is one of the prevalent neurological disorders of the central nervous system hallmarked by increased beta-amyloid (Aβ) deposition and ensuing learning and memory deficit. In the present study, the beneficial effect of naringenin on improvement of learning and memory was evaluated in an Alzheimer's disease rat model. The Aβ-injected rats showed a lower alternation score in Y-maze task, impairment of retention and recall capability in passive avoidance test, and lower correct choices and higher errors in radial arm maze (RAM) task as compared to sham group in addition to enhanced oxidative stress and apoptosis. Naringenin, but not a combination of naringenin and fulvestrant (an estrogenic receptor antagonist) significantly improved the performance of Aβ-injected rats in passive avoidance and RAM tasks. Naringenin pretreatment of Aβ-injected rats also lowered hippocampal malondialdehyde (MDA) with no significant effect on nitrite and superoxide dismutase (SOD) activity in addition to lowering apoptosis. These results suggest naringenin pretreatment attenuates Aβ-induced impairment of learning and memory through mitigation of lipid peroxidation and apoptosis and its beneficial effect is somewhat mediated via estrogenic pathway.

  • 6.
    Hashemi, Mohammad
    et al.
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
    Ghavami, Saeid
    Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada; Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
    Eshraghi, Mehdi
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Booy, Evan P.
    Manitoba Institute of Cell Biology, and Department of Biochemistry and Medical Genetics, Univ. Manitoba, Winnipeg, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Cytotoxic effects of intra and extracellular zinc chelation on human breast cancer cells2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 557, no 1, p. 9-19Article in journal (Refereed)
    Abstract [en]

    Zinc is an essential trace element with cofactor functions in a large number of proteins of intermediary metabolism, hormone secretion pathways, immune defence mechanisms, and as a cofactor of transcription factors it is also involved in the control of gene expression. Our study demonstrates that the modulation of intra and extracellular zinc alone is sufficient to induce metabolic changes or even apoptosis in two model human breast cancer cell lines MCF-7 and MDA-MB468. Treatment of breast cancer cells with different concentrations of a cell membrane permeable zinc chelator, N,N,N'N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and the membrane impermeable zinc chelator, diethylenctriaminepentacetic acid, (DTPA) resulted in a significant increase of cell death. Features of apoptosis, such as chromatin condensation and nuclear fragmentation accompanied the DTPA and TPEN-induced cell death. A significant increase in the activity of caspase-9 was observed in both cell lines; whereas, caspase-3 activity was only increased in MDA-MB468 cells since caspase-3 is not expressed in MCF-7 cells. Caspase-8 activation was negligible in both cell lines. Addition of Zn2+ or Cu2+ prevented DTPA and TPEN-induced cytotoxicity, indicating that both bivalent cations can be replaced functionally to a certain extent in our experimental system. Interestingly, addition of Ca2+, or Mg2+ had no effect. The antioxidant N-Acetyl-L-Cysteine inhibited the cytotoxic effect of DTPA and TPEN, indicating that oxidative stress is the likely mediator of Zn-deficiency-related cell death. (c) 2006 Elsevier B.V. All rights reserved.

  • 7.
    Jonsson, M.
    et al.
    Dept. Anesth. Intensive Care Med., Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden.
    Wyon, Nicholas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care.
    Lindahl, S.G.E.
    Dept. Anesth. Intensive Care Med., Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden.
    Fredholm, B.B.
    Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Eriksson, L.I.
    Dept. Anesth. Intensive Care Med., Karolinska Hospital and Institute, SE-171 76 Stockholm, Sweden.
    Neuromuscular blocking agents block carotid body neuronal nicotinic acetylcholine receptors2004In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 497, no 2, p. 173-180Article in journal (Refereed)
    Abstract [en]

    Neuromuscular blocking agents predominantly block muscle type nicotinic acetylcholine receptors as opposed to the neuronal type. However, there is growing evidence that neuromuscular blocking agents have affinity to some neuronal nicotinic acetylcholine receptors. The carotid body chemoreceptor as the essential oxygen-sensing cell, relies on cholinergic signalling. Atracurium and vecuronium impair carotid body chemoreceptor activity during hypoxia. Here, we characterize atracurium and vecuronium as antagonists at nicotinic receptors of the carotid body chemoreceptor. Isolated rabbit carotid body preparations with carotid sinus nerve were used, and chemoreceptor activities were recorded. There was a concentration-dependent reduction in the chemoreceptor responses to nicotine, with an IC50 to 50 µg nicotine of 3.64 and 1.64 µM and to 500 µg nicotine of 27.00 µM and 7.29 µM for atracurium and vecuronium, respectively. It is concluded that atracurium and vecuronium depress nicotine-induced chemoreceptor responses of the carotid body in a dose-dependent fashion. © 2004 Elsevier B.V. All rights reserved.

  • 8.
    Kälvegren, Hanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Johanna
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Platelet activation triggered by Chlamydia pneumoniae is antagonized by 12-lipoxygenase inhibitors but not cyclooxygenase inhibitors.2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 566, no 1-3, p. 20-27Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae is a respiratory pathogen that has been linked to cardiovascular disease. We have recently shown that C. pneumoniae activates platelets, leading to oxidation of low-density lipoproteins. The aim of the present study was to evaluate the inhibitory effects of different pharmacological agents on platelet aggregation and secretion induced by C. pneumoniae.

    Platelet interaction with C. pneumoniae was studied by analyzing platelet aggregation and ATP-secretion with Lumi-aggregometry.

    Platelet aggregation and ATP-secretion induced by C. pneumoniae was markedly inhibited by the NO-donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), an effect that was counteracted by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Pre-treatment of platelets with the 12-lipoxygenase (12-LOX) inhibitors cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC) and 5,6,7-trikydroxyflavone (baicalein) completely blocked the activation, whereas the cyclooxygenase (COX) inhibitors 2-acetyloxybenzoic acid (aspirin) and (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-9-methyl-10,10-dioxo-10$l^(6)thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one (piroxicam) had no inhibitory effects. Opposite to C. pneumoniae-induced activation, platelets stimulated by collagen were inhibited by the COX-inhibitors but were unaffected by the 12-LOX-inhibitors. The platelet activating factor (PAF) antagonist Ginkgolide B blocked the C. pneumoniae-induced platelet activation, whereas the responses to collagen were unaffected. Furthermore, the P2Y1 and P2Y12 purinergic receptor antagonists 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS2179) and N(6)-(2-methyl-thioethyl)-2-(3,3,3-trifluoropropylthio)-beta,gamma-dichloromethylene-ATP (cangrelor) inhibited the aggregation and secretion caused by C. pneumoniae.

    It is well-known that the efficacy of COX inhibitors in the prevention and treatment of cardiovascular disease varies between different patients, and that patients with low responses to aspirin have a higher risk to encounter cardiovascular events. The findings in this study showing that platelets stimulated by C. pneumoniae are unaffected by COX inhibitors but sensitive to 12-LOX inhibitors, may thus be of importance in future management of atherosclerosis and thrombosis.

  • 9.
    Laskar, Amit
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Miah, Sayem
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways2010In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, no 640, p. 124-128Article in journal (Refereed)
    Abstract [en]

    Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.

  • 10.
    Los, Marek Jan
    Interfaculty Institute for Biochemistry, University of Tübingen, Germany; BioApplications Enterprises, Winnipeg, MB, Canada.
    New, exciting developments in experimental therapies in the early 21st century2009In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 625, no 1-3, p. 1-5Article, review/survey (Refereed)
    Abstract [en]

    The volume is dedicated to novel anticancer strategies. Our aim was to identify and cover novel, emerging anticancer approaches that will form the backbone of future, more efficient anticancer therapies. Beside classical “small molecule” pharmacologic approaches, or radiotherapy, the review introduces cancer stem cell, their markers involved in metastasizing, it covers various immunotherapeutic experimental treatment, inclusive anticancer cellular vaccines, as well as computational strategies aimed at modeling of cancer therapy or at least the intermolecular interactions between drug and the cellular target. Large portion of the volume is dedicated to various targeted anticancer approaches that involve either novel targets within cancer cells (i.e. endoplasmic reticulum and protein folding, or cell–cell adherence), or novel molecules like TRAIL and another human cytokine mda-7/IL-24, Brevinin-2R, viral proteins R4orf4, NS1, and apoptin, HAMLET, onconase, and other molecules. Significant part of the review is also dedicated towards targeting of receptor-initiated and intracellular kinase cascades that are often upregulated in various malignancies. We hope that the variety of topics highlighted in this volume will foster cross-discipline collaborations, so necessary for the development of novel therapeutics.

  • 11.
    Nilsson, J
    et al.
    Karolinska Institute.
    Elinder, Fredrik
    Karolinska Institute.
    Arhem, P
    Karolinska Institute.
    Mechanisms of bupivacaine action on Na+ and K+ channels in myelinated axons of Xenopus laevis1998In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 360, no 1, p. 21-29Article in journal (Refereed)
    Abstract [en]

    The local anaesthetic bupivacaine has recently been proposed to inhibit Na+ channels indirectly by making the resting potential less negative. To test this hypothesis we analysed the effects of bupivacaine on voltage and current clamped nodes of Ranvier. Contrary to the hypothesis, the leak current and the resting potential were unaffected. The Na+ and K+ channels were, however, affected at relatively low concentrations (33 mu M). Steady-state activation curves were decreased without notable shift effects, whereas the Naf inactivation curve was decreased and shifted in negative direction. The effect on the Na+ current was tentatively explained by a single-site, state-dependent binding model (K-d = 44 mu M), while that on the K+ current was explained by two population-specific mechanisms, one open-state dependent (K-d = 550 mu M) and one state independent (K-d = 59 mu M). The binding stoichiometry was higher than 1:1 for the main sites of action. In conclusion, bupivacaine exerts its main anaesthetic action on myelinated nerve axons by a direct modification of Na+ channels.

  • 12.
    Persson, Karin
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nitric oxide modulates captopril-mediated angiotensin-converting enzyme inhibition in porcine iliac arteries1999In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 385, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    The influence of the angiotensin-converting enzyme inhibitor captopril on bradykinin-and angiotensin I-induced responses with special regard to nitric oxide (NO) was studied. Auxometric tension and angiotensin-converting enzyme activity was studied in isolated porcine iliac arteries. Captopril potentiated bradykinin-induced contraction of preparations with intact endothelium; this potentiation was not seen with the kininase I inhibitor mergepta or a bradykinin B1-receptor antagonist. Captopril did not affect bradykinin-induced relaxation. The captopril-mediated increase of bradykinin-induced contraction was only seen in preparations with intact endothelium, while captopril did not affect arterial strips treated with Nω-nitro-L-arginine. Angiotensin I-induced contractions was less reduced by captopril when the strips were pretreated with Nω-nitro-L-arginine. Both captopril and the NO donor S-nitroso-N-acetyl-penicillamine inhibited angiotensin-converting enzyme activity. An additional reduction in angiotensin-converting enzyme activity was seen when S-nitroso-N-acetyl-penicillamine was added to captopril-treated preparations. In conclusion, captopril increased bradykinin-induced contraction in a NO-dependent manner. This potentiation is probably mediated by the increased metabolism of bradykinin by kininase I, and the additive angiotensin-converting enzyme inhibitory effect of captopril and NO.

  • 13.
    Persson, Karin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Whiss, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nyhlén, Kristina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Nursing Science.
    Jacobsson-Strier, M.
    Glindell, M.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Nitric oxide donors and angiotensin-converting enzyme inhibitors act in concert to inhibit human angiotensin-converting enzyme activity and platelet aggregation in vitro2000In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 406, no 1, p. 15-23Article in journal (Refereed)
    Abstract [en]

    This study investigates the effects of exogenous and endogenous nitric oxide (NO) on human circulating and endothelial angiotensin-converting enzyme activity and platelet aggregation. The NO donor S-nitroso-N-acetylpenicillamine (10-8-10-6 M) significantly and dose-dependently inhibited serum angiotensin-converting enzyme activity. The concomitant addition of S-nitroso-N-acetylpenicillamine to angiotensin-converting enzyme inhibitor-treated (captopril or enalaprilat) serum, further reduced angiotensin-converting enzyme activity. In cultured endothelial cells from human umbilical veins (HUVECs), both S-nitroso-N-acetylpenicillamine and 3-morpholinosydnonimine (SIN-1) significantly reduced angiotensin-converting enzyme activity. An additative effect was seen with a combined treatment of captopril and S-nitroso-N-acetylpenicillamine. Treatment with the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) did not affect angiotensin-converting enzyme activity. Thrombin inhibited endothelial angiotensin-converting enzyme activity, an effect that was abolished when cells were pretreated with L-NMMA. Adenosine 5'-diphosphate (ADP)-induced platelet aggregation was inhibited with S-nitroso-N-acetylpenicillamine, SIN-1 and nitroglycerine. Captopril did not affect aggregation, while a high concentration of enalaprilat (10-4 M) reduced it. The concomitant addition of 10-5 M angiotensin-converting enzyme inhibitor to NO donor-treated platelets resulted in a further reduction of platelet aggregation. This effect was most evident with SIN-1 and enalaprilat. In conclusion, both exogenous and endogenous NO inhibit human angiotensin-converting enzyme activity. NO donors and angiotensin-converting enzyme inhibitors act in concert to inhibit angiotensin-converting enzyme and platelet aggregation. Copyright (C) 2000 Elsevier Science B.V.

  • 14.
    Shakirova, Yulia
    et al.
    Department of Experimental Medical Science, Lund University, Biomedical Centre, BMC, Lund, Sweden.
    Hedlund, Petter
    Department of Experimental Medical Science, Lund University, Biomedical Centre, BMC, Lund, Sweden.
    Swärd, Karl
    Department of Experimental Medical Science, Lund University, Biomedical Centre, BMC, Lund, Sweden.
    Impaired nerve-mediated relaxation of penile tissue from caveolin-1 deficient mice2009In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 602, no 2-3, p. 399-405Article in journal (Refereed)
    Abstract [en]

    Caveolin-1-deficient mice are characterised by a high vascular NO production. Because NO-dependent smooth muscle relaxation is considered to play an important role in penile erection, it was hypothesized that the erectile function would be affected by genetic ablation of caveolae. This study assessed penile erectile mechanisms in caveolin-1 knockout (KO) mice ex vivo. Immunofluorescence confirmed caveolin-1 expression primarily in the endothelium surrounding the sinusoids of the corpus cavernosum, but also in smooth muscle cells of the sinusoidal bundles. In KO mice, caveolin-1 was absent, and the expression of the caveola-associated protein PTRF-Cavin was reduced. Nitric oxide synthase (endothelial and neuronal) and caveolin-3 levels were not affected, and staining of the neuronal marker PGP 9.5 did not disclose any apparent change in the density or pattern of innervation. Moreover, no apparent morphological differences were noted. Functionally, the force response following stimulation of alpha(1)-adrenergic receptors, and the sensitivity to the Rho-kinase inhibitor Y27632, were unaltered, whereas relaxation of alpha(1)-precontracted corpus cavernosum in response to electrical field stimulation and the muscarinic agonist carbachol were impaired. The nitric oxide donor sodium nitroprusside produced less relaxation in KO as compared to wild type corpus cavernosum. We conclude that nerve-mediated dilatation of the corpus cavernosum is impaired in the absence of caveolin-1, and that this is due in part to reduced sensitivity of the target tissue to NO. All in all our data support an important role of caveolin-1 in penile erection.

  • 15.
    Strittmatter, Frank
    et al.
    Department of Urology, University of Munich, Munich, Germany.
    Gratzke, Christian
    Department of Urology, University of Munich, Munich, Germany.
    Weinhold, Philipp
    Department of Urology, University of Munich, Munich, Germany.
    Steib, Christian J.
    Department of Medicine II, University of Munich, Munich, Germany.
    Hartmann, Anna C.
    Department of Medicine II, University of Munich, Munich, Germany.
    Schlenker, Boris
    Department of Urology, University of Munich, Munich, Germany.
    Andersson, Karl-Erik
    Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA.
    Hedlund, Petter
    Department of Clinical and Experimental Pharmacology, Lund University, Sweden.
    Stief, Christian G
    Department of Urology, University of Munich, Munich, Germany.
    Hennenberg, Martin
    Department of Urology, University of Munich, Munich, Germany.
    Thromboxane A2 induces contraction of human prostate smooth muscle by Rho kinase- and calmodulin-dependent mechanisms2011In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 650, no 2-3, p. 650-655Article in journal (Refereed)
    Abstract [en]

    Thromboxane A(2) (TXA(2)) induces contraction in different smooth muscle types via its receptor (TXA(2) receptor). However, any motoric role of TXA(2) in prostate smooth muscle tone has not been studied to date. Here, we investigated whether TXA(2) induces contraction of human prostate tissue. After ethical approval, prostate tissue was obtained from 47 patients undergoing radical prostatectomy. Effects of the TXA(2) analogue U46619 ((5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptonic acid) in isolated human prostate strips were studied in organ bath experiments with or without the Rho kinase inhibitor, Y27632 (trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide dihydrochloride), or the calmodulin antagonist W7 (N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride). Expression of TXA(2) synthase and TXA(2) receptors were examined by Western blot analysis and immunohistochemistry. Endogenous TXA(2) was quantified by enzyme immunoassay. U46619 induced concentration-dependent contractions of human prostate strips, with a maximum contraction at 3 μM. U46619-induced prostate contraction was significantly inhibited by Y27632 (30 μM) and by W7 (100 μM). TXA(2) synthase and TXA(2) receptors were detected by Western blot analysis. Immunohistochemical stainings showed that expression of TXA(2) synthase in prostate tissue was located to glandular cells, while prostate TXA(2) receptors were located to smooth muscle and glandular cells. The stable TXA(2) metabolite TXB(2) was detected by enzyme immunoassay in the prostate. TXA(2) induces contraction of isolated human prostate tissue by TXA(2) receptor activation. Prostate smooth muscle TXA(2) receptors are coupled to Rho kinase and Ca(2+)-dependent mechanisms. The distribution of TXA(2) synthase and TXA(2) receptors in the human prostate suggests TXA(2)-mediated paracrine epithelial-stromal interactions.

  • 16.
    Voss, Logan J
    et al.
    Waikato District Health Board.
    Brock, Magdalena
    Linköping University, Faculty of Health Sciences.
    Carlsson, Cecilia
    Linköping University, Faculty of Health Sciences.
    Steyn-Ross, Alistair
    University of Waikato.
    Steyn-Ross, Moira
    University of Waikato.
    W Sleigh, James
    Waikato District Health Board.
    Investigating paradoxical hysteresis effects in the mouse neocortical slice model2012In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 675, no 1-3, p. 26-31Article in journal (Refereed)
    Abstract [en]

    Clinically, anesthetic drugs show hysteresis in the plasma drug concentrations at induction versus emergence from anesthesia induced unconsciousness. This is assumed to be the result of pharmacokinetic lag between the plasma and brain effect-site and vice versa. However, recent mathematical and experimental studies demonstrate that anesthetic hysteresis might be due in part to lag in the brain physiology, independent of drug transport delay-so-called "neural inertia". The aim of this study was to investigate neural inertia in the reduced neocortical mouse slice model. Seizure-like event (SLE) activity was generated by exposing cortical slices to no-magnesium artificial cerebrospinal fluid (aCSF). Concentration-effect loops were generated by manipulating SLE frequency, using the general anesthetic drug etomidate and by altering the aCSF magnesium concentration. The etomidate (24 mu M) concentration-effect relationship showed a clear hysteresis, consistent with the slow diffusion of etomidate into slice tissue. Manipulation of tissue excitability, using either carbachol (50 mu M) or elevated potassium (5 mM vs 2.5 mM) did not significantly alter the size of etomidate hysteresis loops. Hysteresis in the magnesium concentration-effect relationship was evident, but only when the starting condition was magnesium-containing "normal" aCSF. The in vitro cortical slice manifests pathway-dependent "neural inertia" and may be a valuable model for future investigations into the mechanisms of neural inertia in the cerebral cortex.

  • 17.
    Voss, Logan J.
    et al.
    Waikato Dist Health Board, New Zealand .
    Hansson Baas, Cecilia
    Linköping University, Faculty of Health Sciences.
    Hansson, Linnea
    Linköping University, Faculty of Health Sciences.
    Steyn-Ross, D. Alistair
    University of Waikato, New Zealand .
    Steyn-Ross, Moira
    University of Waikato, New Zealand .
    Sleigh, James W.
    University of Auckland, New Zealand .
    Investigation into the effect of the general anaesthetics etomidate and ketamine on long-range coupling of population activity in the mouse neocortical slice2012In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 689, no 1-3, p. 111-117Article in journal (Refereed)
    Abstract [en]

    General anaesthetics have been hypothesised to ablate consciousness by decoupling intracortical neural connectivity. We explored this by investigating the effect of etomidate and ketamine on coupling of neural population activity using the low magnesium neocortical slice model. Four extracellular electrodes (50 mu m) were positioned in mouse neocortical slices (400 mu m thick) with varying separation. The effect of etomidate (24 mu M) and ketamine (16 mu M) on the timing of population activity recorded between channels was analysed. No decoupling was observed at the closest electrode separation of 0.2 mm. At 4 mm separation, decoupling was observed in 50% and 42% of slices during etomidate and ketamine delivery, respectively (P less than 0.0001 and P=0.002, compared to 0.2mm separation). A lower rate of decoupling was observed with 1 mm separation (21% and 8%, respectively, P less than 0.03 for etomidate compared to 0.2 mm separation). The data support the hypothesis that mechanistically diverse general anaesthetics disrupt neuronal connectivity across widely distributed intracortical networks.

  • 18.
    Wiechec, Emilia
    et al.
    University of Aarhus, Denmark.
    Hansen, Lise Lotte
    University of Aarhus, Denmark.
    The effect of genetic variability on drug response in conventional breast cancer treatment2009In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 625, no 1-3, p. 122-130Article, review/survey (Refereed)
    Abstract [en]

    The conventional breastcancer diagnosis based mainly upon histopathology, hormone and HER-2 receptor status, will in the future be combined with information on genomic and epigenetic profiles of the individual patient. This will lead to an optimal personalized therapy, directed towards specific genomic aberrations, avoiding unnecessary toxicity, side effects and chemotherapeutic drugs for which the patient evolves resistance. Breastcancer is a very heterogeneous malignancy, expressing a considerable variation in genomic aberrations from deletions and amplifications comprising entire chromosomes to minor regions. A wide spectrum of differently expressed genes and mutations has been identified, adding information to the highly complex picture of the tumor genome. The vast majority of breastcancer incidents is of somatic origin and may be caused by a combination of the individual genetic profile and environmental exposure. A major contributor to the variation in genetic profile is the single nucleotide polymorphisms (SNPs), which are highly abundant throughout the genome, and both current and future methodologies have the potential to screen millions of SNP genotypes in one analysis. Identification of specific SNP genotypes affecting transcriptional activity and thereby the outcome for the patient, of genes involved in DNA repair, metabolizing of chemotherapeutic drugs and drug target genes will determine the outcome for the patient. This will be an essential part of the development of personalized treatment of cancer. In this review the focus is on clinically relevant SNPs in genes implicated in drug metabolism and disposition as well as their influence on breastcancer therapy toxicity and/or efficacy.

  • 19.
    Zuse, Ann
    et al.
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany; Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, Winnipeg, Canada.
    Prinz, Helge
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Müller, Klaus
    Institute of Medicinal and Pharmaceutical Chemistry, Westphalian Wilhelms-University, Hittorfstrasse 58-62, D-48149 Münster, Germany.
    Schmidt, Peter
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Günther, Eckhard G.
    Zentaris GmbH, Weismüllerstrasse 50, D-60314 Frankfurt, Germany.
    Schweizer, Frank
    Department of Chemistry, Univ. Manitoba, Winnipeg, Canada.
    Prehn, Jochen H.M.
    Department of Physiology and RCSI Research Institute, St. Stephen's Green, Dublin, Ireland.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    9-benzylidene-naphtho[2,3-b]thiophen-4-ones and benzylidene-9(10H)-anthracenones as novel tubulin interacting agents with high apoptosis-inducing activity2007In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 575, no 1-3, p. 34-45Article in journal (Refereed)
    Abstract [en]

    Tubulin-binding 9-benzylidene-naphtho[2,3-b]thiophen-4-ones 1a and 1b and benzylidene-9(10H)-anthracenone 2 were evaluated for their ability to induce cell death. We examined the effect of the molecules on cell cycle progression, organization of microtubule networks, and apoptosis induction. As determined by flow cytometry, cancer cells were predominantly arrested in metaphase with 4N DNA before cell death occurred. By using indirect immunofluorescence techniques we visualized microtubule depolymerization recognizable by short microtubule fragments scattered around the nucleus. The incubation with 1a and 2 resulted in chromatin condensation, nuclear fragmentation, and cell shrinkage, which are, among others, typical features of apoptotic cell death. Furthermore, time- and dose-dependent induction of apoptosis in SH-SY5Y cells was detected via cleavage of Ac-DEVD-AMC, a fluorigenic substrate for caspase-3. We observed a lower apoptotic activity in neuroblastoma cells overexpressing Bcl-xL, suggesting activation of the mitochondrial apoptosis pathway. Western blot analysis demonstrated that caspase-3, an apoptosis mediator, was activated in a time-dependent manner after exposure of SH-SY5Y cells to drugs 1a and 2. Taken together, the agents investigated in the present study display strong apoptosis-inducing activity and therefore show promise for the development of novel chemotherapeutics.

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