Han, Xinqiang;
Kubota, Isao;
Feron, Olivier;
Opel, Douglas J.;
Arstall, Margaret A.;
Zhao, You-Yang;
Huang, Paul;
Fishman, Mark C.;
Michel, Thomas;
Kelly, Ralph A.
Muscarinic Cholinergic Regulation of Cardiac Myocyte ICa-Lis Absent in Mice with Targeted Disruption of Endothelial Nitric Oxide Synthase
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Media type:
E-Article
Title:
Muscarinic Cholinergic Regulation of Cardiac Myocyte ICa-Lis Absent in Mice with Targeted Disruption of Endothelial Nitric Oxide Synthase
Contributor:
Han, Xinqiang;
Kubota, Isao;
Feron, Olivier;
Opel, Douglas J.;
Arstall, Margaret A.;
Zhao, You-Yang;
Huang, Paul;
Fishman, Mark C.;
Michel, Thomas;
Kelly, Ralph A.
Published:
National Academy of Sciences of the United States of America, 1998
Published in:
Proceedings of the National Academy of Sciences of the United States of America, 95 (1998) 11, Seite 6510-6515
Language:
English
ISSN:
0027-8424
Origination:
Footnote:
Description:
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-Land contractile amplitude in isoproterenol (ISO)-prestimulated ventricular myocytes isolated from adult mice, designated eNOSnullmice, with targeted disruption of the eNOS gene. Although both eNOSnulland wild-type (WT) ventricular myocytes exhibited similar increases in ICa-Lin response to ISO, there was no measurable suppression of ICa-Lby CCh in cells from eNOSnullmice, 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 eNOSnullmyocytes. Also, unlike myocytes from WT animals, eNOSnullmyocytes 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-Lin eNOSnullcells, suggesting that the signal transduction pathway(s) downstream of eNOS remained intact. Of importance, activation of the acetylcholine-activated K+channel by CCh was unaffected in atrial and ventricular eNOSnullmyocytes. These results confirm the obligatory role of eNOS in coupling muscarinic receptor activation to cGMP-dependent control of ICa-Lin cardiac myocytes.