Abstract
Sympathetic activation during acute myocardial infarction (MI) is an important arrhythmogenic mechanism, but the role of central autonomic inputs and their modulating factors remain unclear. Using the in vivo rat-model, we examined the effects of clonidine, a centrally acting sympatholytic agent, in the presence or absence of myocardial endothelin-B (ETB) receptors. We studied wild-type (n = 20) and ETB-deficient rats (n = 20) after permanent coronary ligation, with or without pretreatment with clonidine. Cardiac rhythm was continuously recorded for 24 h by implantable telemetry devices, coupled by the assessment of autonomic and heart failure indices. Sympathetic activation and arrhythmogenesis were more prominent in ETB-deficient rats during the early phase post-ligation. Clonidine improved these outcomes throughout the observation period in ETB-deficient rats, but only during the delayed phase in wild-type rats. However, this benefit was counterbalanced by atrioventricular conduction abnormalities and by higher incidence of heart failure, the latter particularly evident in ETB-deficient rats. Myocardial ETB-receptors attenuate the arrhythmogenic effects of central sympathetic activation during acute MI. ETB-receptor deficiency potentiates the sympatholytic effects of clonidine and aggravates heart failure. The interaction between endothelin and sympathetic responses during myocardial ischemia/infarction and its impact on arrhythmogenesis and left ventricular dysfunction merits further investigation.
Highlights
Sudden cardiac death (SCD) accounts for 13% of total mortality from natural causes in the general population and has emerged as an important health-related problem
SCD is caused by ventricular tachyarrhythmias, i.e., ventricular tachycardia (VT) and ventricular fibrillation (VF), triggered by acute myocardial infarction (MI) [1]
The role of sympathetic activation in the pathogenesis of VT/VF during acute MI has been known for decades [2]; myocardial ischemia leads to local norepinephrine release from sympathetic nerve terminals, primarily via non-exocytotic mechanisms, following an immediate exocytotic phase [3]
Summary
Sudden cardiac death (SCD) accounts for 13% of total mortality from natural causes in the general population and has emerged as an important health-related problem. The role of sympathetic activation in the pathogenesis of VT/VF during acute MI has been known for decades [2]; myocardial ischemia leads to local norepinephrine release from sympathetic nerve terminals, primarily via non-exocytotic mechanisms, following an immediate exocytotic phase [3]. The elicited positive inotropic response serves the maintenance of cardiac output, but local catecholamine surge alters ventricular electrophysiological properties and creates an arrhythmogenic milieu [4]. These mechanisms may predominate during the early period post-MI, corresponding clinically to the critical pre-hospital stage, during which VT/VF carries a dismal prognosis [1]
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