THE ROLE OF TRPV4 CATION CHANNELS IN THE REGULATION OF PHENYLEPHRINE-INDUCED CONTRACTION OF RAT PULMONARY ARTER.

Abstract

The aim of our study was to investigate the role of mechanosensitive TRPV4 channels in the regulation of rat pulmonary artery smooth muscle (PASM) contractile activity induced by the activation of α-adrenoceptors and the possibility of their use as novel pharmacological targets in pulmonary hypertension. TRPV4 selective agonist, GSK1016790A, in the presence of the agonist of α-adrenoceptors phenylephrine (PhE) evoked biphasic contractile reaction with initial relaxation (63,5% ± 7,1) followed by significant vasoconstriction (142% ± 17,9). GSK1016790A evoked similar effects in PASM rings with and without endothelium, 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 these 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 reaction could be explained as an initial calcium store depletion by PhE and further calciuminduced calcium release activated by TRPV4 that causes BKCa activation, membrane hyperpolarisation and vasorelaxation, followed by Ca2+ entry via TRPV4 and contraction. We conclude that TRPV4 channels play an important role in the regulation of the adrenergic vascular tone of PASM cells, but TRPV4 activation mechanism(s) and signaling pathways remain unclear.