Role of nitric oxide in the regulation of mechanosensitive ionic channels in cardiomyocytes: contribution of NO-synthases.

摘要

The role of NO in the regulation of currents passing through ion channels activated by cell stretching (mechanically gated channels, MGC), particularly through cation-selective K(+)-channels TRPC6, TREK1 (K(2P)2.1), and TREK2 (K(2P)10.1), was studied on isolated mouse, rat, and guinea pig cardiomyocytes using whole-cell patch-clamp technique. In non-deformed cells, binding of endogenous NO with PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-1-oxy-3-oxide) irreversibly shifted the diastolic membrane potential towards negative values, modulates K(ir)-channels by reducing I(K1), and blocks MGC. Perfusion of stretched cells with PTIO solution completely blocked MG-currents. NO-synthase inhibitors L-NAME and L-NMMA completely blocked MGC. Stretching of cardiomyocytes isolated from wild type mice and from NOS1(-/-)- and NOS2(-/-)- knockout mice led to the appearance in MG-currents typical for the specified magnitude of stretching, while stretching of cardiomyocytes from NOS3(-/-)- knockout mice did not produce in MG-current. These findings suggest that NO plays a role in the regulation of MGC activity and that endothelial NO-synthase predominates as NO source in cardiomyocyte response to stretching.