Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart.

Abstract

Human heart failure is associated with a diminished contractile response to 0-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (aG40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (G.). The increased activity in aG40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased aG40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to 01-adrenergic agonists in the failing human heart.

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

“…Previous studies have shown that muscarinic receptor density in myocardium from patients with end-stage heart failure is unchanged as compared to receptor density in normal myocardium (13)(14)(15), but that G i activity is increased (15)(16)(17). The results of the present study provide insight into the function of muscarinic pathways in the setting of human congestive heart failure.…”

“…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.…”

“…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.…”