RESUMO
Depolarization of cardiomyocytes triggered by stretch and activation of mechanically gated ion channels can lead to serious arrhythmias. However, stretch-induced signaling activating these channels remain little studied. This study tested the hypothesis on implication of NO in shaping the electrical abnormalities provoked by stretch of the right atrial myocardium in rat via a mechanism engaging a signaling cascade, where NO plays a significant role. This approach showed that in isolated right atrial preparation, NO donor SNAP induces the electrical abnormalities similar to those provoked by stretch, and the latter results from activation of NO synthase.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Função Atrial/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , S-Nitroso-N-Acetilpenicilamina/farmacologia , Potenciais de Ação/fisiologia , Animais , Fenômenos Biomecânicos , Feminino , Gadolínio/farmacologia , Canais Iônicos/antagonistas & inibidores , Canais Iônicos/metabolismo , Miócitos Cardíacos/fisiologia , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Nó Sinoatrial/efeitos dos fármacos , Nó Sinoatrial/fisiologia , Técnicas de Cultura de TecidosRESUMO
Whole-cell ionic currents through mechanically gated channels (MGC) were recorded in isolated cardiomyocytes under voltage clamp conditions. In unstrained cells, NO donors SNAP and DEA-NO activated MGC and induced MG-like currents. In contrast, in stretched cells with activated MGC, these NO-donors inactivated and inhibited MGC.
Assuntos
Ativação do Canal Iônico/efeitos dos fármacos , Canais Iônicos/metabolismo , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Animais , Células Cultivadas , Cobaias , Hidrazinas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , S-Nitroso-N-Acetilpenicilamina/farmacologiaRESUMO
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.
