Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety |
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Authors: | CF Samer Y Daali M Wagner G Hopfgartner CB Eap MC Rebsamen MF Rossier D Hochstrasser P Dayer JA Desmeules |
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Institution: | 1.Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;2.Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;3.International University of Health and Welfare, Fukuoka, Japan |
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Abstract: | Background and purpose:Thrombus formation is commonly associated with pulmonary arterial hypertension (PAH). Thrombin may thus play an important role in the pathogenesis and pathophysiology of PAH. Hence, we investigated the contractile effects of thrombin and its mechanism in pulmonary artery.Experimental approach:The cytosolic Ca2+ concentrations (Ca2+]i), 20 kDa myosin light chain (MLC20) phosphorylation and tension development were evaluated using the isolated porcine pulmonary artery.Key results:Thrombin induced a sustained contraction in endothelium-denuded strips obtained from different sites of a pulmonary artery, ranging from the main pulmonary artery to the intrapulmonary artery. In the presence of endothelium, thrombin induced a transient relaxation. The contractile effect of thrombin was abolished by either a protease inhibitor or a proteinase-activated receptor 1 (PAR1) antagonist, while it was mimicked by PAR1-activating peptide (PAR1AP), but not PAR4AP. The thrombin-induced contraction was associated with a small elevation of Ca2+]i and an increase in MLC20 phosphorylation. Thrombin and PAR1AP induced a greater increase in tension for a given Ca2+]i elevation than that obtained with high K+-depolarization. They also induced a contraction at a fixed Ca2+ concentration in α-toxin-permeabilized preparations.Conclusions and implications:The present study revealed a unique property of the pulmonary artery. In contrast to normal arteries of the systemic circulation, thrombin induces a sustained contraction in the normal pulmonary artery, by activating PAR1 and thereby increasing the sensitivity of the myofilament to Ca2+. This responsiveness of the pulmonary artery to thrombin may therefore contribute to the pathogenesis and pathophysiology of PAH. |
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Keywords: | pulmonary artery thrombin vasoconstriction proteinase-activated receptor 1 Ca2+ sensitivity myosin light chain phosphorylation |
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