Role of nitric oxide in the regulation of mechanosensitive ionic channels in cardiomyocytes: contribution of NO-synthases.
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.
Department of Fundamental and Applied Physiology, N I Pirogov Russian State Medical University, Moscow, Russia.
V E
VE
Kazanski
A G
AG
Kamkin
E Yu
EY
Makarenko
N N
NN
Lysenko
P V
PV
Sutiagin
I S
IS
Kiseleva
D000704:Analysis of Variance; D000818:Animals; D003497:Cyclic N-Oxides / Q000378:metabolism; D006168:Guinea Pigs; D007093:Imidazoles / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019323:omega-N-Methylarginine / Q000494:pharmacology
D003497:Cyclic N-Oxides; D007093:Imidazoles; D015221:Potassium Channels; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester