Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy.

Abstract

(Circulation 1990;82:1249-1265 H eart failure is characterized as inadequate cardiac output during exercise or rest, which is accompanied by a number of compensatory mechanisms. One of these is the activation of the sympathetic nervous system' to maintain cardiac output and perfusion pressure. The consequences of these processes are increased levels of catecholamines in the blood,2-4 which are related to the severity of symptoms and prognosis3 of patients with heart failure. The increased sympathetic tone imposes a permanent 83-adrenergic stimulus upon the heart, which leads to downregulation of cardiac ,8-adrenoceptors5-7 and a blunted positive inotropic response to 3-adrenoceptor agonists.5-10 There is also a reduced responsiveness of the failing myocardium to other cAMP-dependent positive inotropic compounds, such as phosphodiesterase inhibitors8-10

Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

“…Muscarinic stimulation may have activated the inhibitory G protein, G i , leading to reduced adenylate cyclase production of cAMP (25). This may be relevant in the setting of heart failure, where G i activity is increased (5,(15)(16)(17)(18). The effects of acetylcholine may have been secondary to stimulation of inhibitory muscarinic receptors on adrenergic nerve terminals (6,26).…”

“…Alternatively, the negative lusitropic response to acetylcholine may be explained by increased sensitivity to muscarinic stimulation in the setting of heart failure (5). This might occur because of increased muscarinic receptor density (5,12), or because of an increase in G i activity in the setting of heart failure (5,(15)(16)(17)(18). The negative lusitropic effect of acetylcholine may also have resulted from non cAMP-dependent mechanisms including effects on phospholamban phosphorylation (30), and phospholipase C (13), which could stress an already impaired calcium handling system in heart failure (31).…”

“…Muscarinic receptors couple to the inhibitory G protein, G i , which has increased activity in the failing heart (5,(15)(16)(17)(18). Vatner et al (5) have recently confirmed that heart failure, induced by rapid ventricular pacing in dogs, is associated with an increase in muscarinic receptor density and G i in ventricular myocardium.…”

“…In various animal models of heart failure muscarinic receptor density in ventricular myocardium has been reported to be either reduced (10,11) or increased (5,12), while receptor density in cardiac tissue from patients with heart failure has been shown to be unchanged (13)(14)(15). Muscarinic receptors couple to the inhibitory G protein, G i , which has increased activity in the failing heart (5,(15)(16)(17)(18).…”

“…Given normal receptor density (13)(14)(15), increased G i activity (5,(15)(16)(17)(18), and the negative inotropic effects of muscarinic stimulation in an animal model of heart failure (5), muscarinic receptor modulation may have important effects on ventricular function in human congestive heart failure. Therefore, this study was performed to determine the effect of myocardial muscarinic receptor modulation on basal and dobutamine stimulated left ventricular systolic and diastolic function in patients with heart failure, and to contrast these effects with observations made in subjects with normal ventricular function.…”