Mechanosensitive nonselective cation channel facilitation by endothelin-1 is regulated by protein kinase C in arterial myocytes

Objective: The mechanosensitive nonselective cation channel (NSCMS) and endothelin-1 (ET-1) play critical roles in the regulation of vascular tone. This study was undertaken to investigate the effect of ET-1 on NSCMS and on the myogenic response of arteries. Methods: Cell-attached patch-clamp techniques were applied to rabbit pulmonary and cerebral arterial smooth muscle cells using a 140 mM CsCl pipette and bath solutions (Ca2+-free, 1 mM EGTA). Myogenic responses were determined by video analysis of pressurized arteries. Results: The application of negative pressures through the pipette activated NSCMS, and this was augmented by bath application of ET-1 (1 pM-30 nM). ET-1 lowered the lowest pressure required for NSCMS activation. NSCMS facilitation by ET-1 was prevented by BQ-123 (1 mu M, an ETA antagonist) but not by BQ-788 (1 mu M, an ETB antagonist). Phorbol 12-myristate 13-acetate (PMA, 100 mu M), a protein kinase C activator, also increased the activity of NSCMS. ET-1- or PMA-induced facilitation of NSCMS was abolished by GF 109203X (10 mu M), a protein kinase C inhibitor. Video analysis of pressurized cerebral artery showed inhibition of the myogenic response by the NSCMS channel blockers GsMTx-4 (5 mu M) and DIDS (3-100 mu M). Treatment with ET-1 (10 pM) augmented the myogenic response and this was inhibited by DIDS (30 mu M). Conclusion: Stimulation of ET-1 receptor (ETA) facilitates NSCMS via a protein kinase C-dependent signaling pathway in rabbit arterial myocytes. Our findings suggest that NSCMS play a role in the myogenic response and its augmentation by ET-1. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.