TY - JOUR
T1 - Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase
AU - Kubota, Isao
AU - Han, Xinqiang
AU - Opel, Douglas J.
AU - Zhao, You Yang
AU - Baliga, Ragaven
AU - Huang, Paul
AU - Fishman, Mark C.
AU - Shannon, Richard P.
AU - Michel, Thomas
AU - Kelly, Ralph A.
N1 - Funding Information:
This study was supported in part by NIH grant H52320. Dr Isao Kubota was supported by a visiting scholarship from Japan. The authors wish to thank Xiao-Fen Lou for assistance with cell isolation.
PY - 2000
Y1 - 2000
N2 - Nitric oxide generated by cardiac myocytes or delivered by drugs has been shown to regulate cardiac contractile function and has been implicated in suppressing some cardiac arrhythmias, although this remains controversial. We examined the ability of the soluble cardiac glycoside, ouabain, to trigger arrhythmic contractions in ventricular myocytes isolated from mice lacking a functional endothelial nitric oxide synthase gene (eNOS(null)). Arrhythmic activity, defined as aftercontractions, was induced with ouabain (50 μmol/L) and recorded using a video-motion detector in isolated, electrically driven single ventricular myocytes from adult eNOS(null) or from their wild-type (WT) littermates. The rate of ouabain-induced arrhythmic contractions was significantly higher in eNOS(null) myocytes than in WT myocytes. Application of the NO donor S-nitroso-acetylcysteine (SNAC) significantly diminished the frequency of arrhythmic contractions in eNOS(null) myocytes. The antiarrhythmic effect of NO, whether generated by eNOS in WT cells or by SNAC, could be partially reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a specific soluble guanylyl cyclase inhibitor. Ouabain significantly increased intracellular cGMP in WT but not eNOS(null) hearts, and this cGMP response was blocked by ODQ. Since cardiac glycoside-induced aftercontractions are activated by the transient inward current (I(ti)), the role of NO in ouabain (100 μmol/L)-induced I(ti) was examined using the nystatin-perforated patch - clamp technique. The frequency of ouabain-induced I(ti) was significantly higher in eNOS(null) myocytes than in WT myocytes, and this could be suppressed by SNAC. These data demonstrate that NO derived from myocyte eNOS activation suppresses ouabain-induced arrhythmic contractions by a mechanism that might involve activation of guanylyl cyclase and elevation of cGMP. (C) 2000 Academic Press.
AB - Nitric oxide generated by cardiac myocytes or delivered by drugs has been shown to regulate cardiac contractile function and has been implicated in suppressing some cardiac arrhythmias, although this remains controversial. We examined the ability of the soluble cardiac glycoside, ouabain, to trigger arrhythmic contractions in ventricular myocytes isolated from mice lacking a functional endothelial nitric oxide synthase gene (eNOS(null)). Arrhythmic activity, defined as aftercontractions, was induced with ouabain (50 μmol/L) and recorded using a video-motion detector in isolated, electrically driven single ventricular myocytes from adult eNOS(null) or from their wild-type (WT) littermates. The rate of ouabain-induced arrhythmic contractions was significantly higher in eNOS(null) myocytes than in WT myocytes. Application of the NO donor S-nitroso-acetylcysteine (SNAC) significantly diminished the frequency of arrhythmic contractions in eNOS(null) myocytes. The antiarrhythmic effect of NO, whether generated by eNOS in WT cells or by SNAC, could be partially reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a specific soluble guanylyl cyclase inhibitor. Ouabain significantly increased intracellular cGMP in WT but not eNOS(null) hearts, and this cGMP response was blocked by ODQ. Since cardiac glycoside-induced aftercontractions are activated by the transient inward current (I(ti)), the role of NO in ouabain (100 μmol/L)-induced I(ti) was examined using the nystatin-perforated patch - clamp technique. The frequency of ouabain-induced I(ti) was significantly higher in eNOS(null) myocytes than in WT myocytes, and this could be suppressed by SNAC. These data demonstrate that NO derived from myocyte eNOS activation suppresses ouabain-induced arrhythmic contractions by a mechanism that might involve activation of guanylyl cyclase and elevation of cGMP. (C) 2000 Academic Press.
KW - Calcium overload
KW - Digitalis glycoside
KW - Nitric oxide synthase
KW - Transient inward current
KW - Triggered arrhythmia
KW - cGMP
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U2 - 10.1006/jmcc.2000.1158
DO - 10.1006/jmcc.2000.1158
M3 - Article
C2 - 10860766
AN - SCOPUS:0033847936
SN - 0022-2828
VL - 32
SP - 1239
EP - 1248
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 7
ER -