Muscarinic cholinergic regulation of cardiac myocyte I Ca-L is absent in mice with targeted disruption of endothelial nitric oxide synthase

作者：Xinqiang Han, Isao Kubota, Olivier Féron, Douglas J. Opel, Margaret A. Arstall, You‐Yang Zhao, Paul Lee Huang, Mark C. Fishman, Thomas M. Michel, Ralph A. Kelly · 发表于：Proceedings of the National Academy of Sciences · 年份：1998 · DOI：10.1073/pnas.95.11.6510 · 被引用次数：146 · 研究领域：Ion channel regulation and function、Cardiac electrophysiology and arrhythmias、Receptor Mechanisms and Signaling

Cardiac myocytes have been shown to express constitutively endothelial nitric oxide synthase (eNOS) (nitric oxide synthase 3), the activation of which has been implicated in the regulation of myocyte L-type voltage-sensitive calcium channel current (ICa-L) and myocyte contractile responsiveness to parasympathetic nervous system signaling, although this implication remains controversial. Therefore, we examined the effect of the muscarinic cholinergic agonist carbachol (CCh) on ICa-L and contractile amplitude in isoproterenol (ISO)-prestimulated ventricular myocytes isolated from adult mice, designated eNOSnull mice, with targeted disruption of the eNOS gene. Although both eNOSnull and wild-type (WT) ventricular myocytes exhibited similar increases in ICa-L in response to ISO, there was no measurable suppression of ICa-L by CCh in cells from eNOSnull mice, in contrast to cells from WT mice. These results were reflected in the absence of an effect of CCh on the positive inotropic effect of ISO in eNOSnull myocytes. Also, unlike myocytes from WT animals, eNOSnull myocytes failed to exhibit an increase in cGMP content in response to CCh. Nevertheless, the pharmacologic nitric oxide donors 3-morpholino-sydnonimine and S-nitroso-acetyl-cystein increased cGMP generation and suppressed ISO-augmented ICa-L in eNOSnull cells, suggesting that the signal transduction pathway(s) downstream of eNOS remained intact. Of importance, activation of the acetylcholine-activated K+ channel by CCh w...