RT Journal Article ID 4750ea9f449db58c A1 Dryn, Dariia A1 Melnyk, Mariia A1 Kizub, Ihor A1 Hu, Hongzhen A1 Soloviev, Anatoly I. A1 Zholos, Alexander T1 The Role of TRPV4 Cation Channels in Regulation of Phenylephrine-Induced Contraction of Rat Pulmonary Artery JF International Journal of Physiology and Pathophysiology JO IJPP YR 2017 FD 2017-08-24 VO 8 IS 2 SP 121 OP 130 K1 vascular smooth muscle K1 pulmonary artery K1 transient receptor potential channels K1 TRPV4 agonist and antagonist K1 vasodilatation K1 vasoconstriction AB The aim of the study was to investigate the role of vanilloid transient receptor potential cation channel (TRPV4) in the regulation of rat pulmonary artery smooth muscle (PASM) contractile activity induced by the activation of α1-adrenoceptors and study them as a potential target for pharmacological intervention in pulmonary hypertension. TRPV4 selective agonist, GSK1016790A, in the presence of the α1-adrenoceptor agonist phenylephrine (PhE) evoked biphasic contractile reaction with initial relaxation (63.5% ± 7.1) followed by a significant vasoconstriction (142% ± 17.9%). GSK1016790A evoked similar effects on the PASM rings with endothelium and without it, indicating that its main site of action was TRPV4 expressed in smooth muscle cells. TRPV4 selective blocker, HC-067047, completely inhibited the effects of GSK1016790A confirming the specific role of TRPV4 in those vascular responses. Application of Ca2+-free external solution reduced the relaxation phase and completely abolished the sustained contractile response to GSK1016790A (from 43.9% to 0.3%). The biphasic dilation-constriction response could be explained by an initial calcium store depletion by PhE and further calcium-induced calcium release from the sarcoplasmic reticulum through TRPV4 channels to cause BKCa activation, membrane hyperpolarisation and vasorelaxation. Further Ca2+ entry via TRPV4 channels causes contraction. We have concluded that TRPV4 channels play an important role in the regulation of the pulmonary artery vascular tone, but TRPV4 activation mechanism(s) and signaling pathways remain unclear. PB Begell House LK https://www.dl.begellhouse.com/journals/6ec4ba27650016b1,4a1e5fe11470826b,4750ea9f449db58c.html