Transregulation of adenylyl-cyclase-coupled inhibitory receptors in heart failure enhances anti-adrenergic effects on adult rat cardiomyocytes

Objective: In congestive heart failure (CHF), a desensitisation of stimulat ory beta-receptors and of adenylyl cyclase in the heart is associated with an increase in inhibitory G(i) proteins. To investigate whether the regulat ion of the G(i)-mediated inhibitory side of the adenylyl cyclase system may be of functional importance in the failing myocardium, the contractile res ponse of isolated adult cardiomyocytes to stimulation of inhibitory muscari nic M-2 and A(1) adenosine receptors was analysed. Methods: CHF was induced in rats by banding of the ascending aorta and was verified by doubling of lung wet weight. After four weeks, contraction amplitude (Delta L) and the velocity (dL/dt(max)) of isolated ventricular cardiomyocytes during electri cal field stimulation in the presence of 1 mM Ca2+ were measured using vide o micrometry. Results: Contractile responses of failing cardiomyocytes to 5 mM Ca2+ were unchanged. The response to increasing concentrations of the b eta-adrenergic agonist, isoproterenol (0.1-30 nM), and to forskolin (0.1 nM -1 mu M) were significantly blunted. When A(1) receptors were activated wit h N-6-(R-phenyl-isopropyl)-adenosine (PIA; 0.01-1 mu M) in the presence of 3 nM isoproterenol, contractility was unchanged in cells compared with thos e from sham-operated rats, but Delta L was reduced by up to 23% and dL/dt(m ax) by 35% in failing cardiomyocytes (P<0.01), demonstrating an enhanced in hibitory effect of A(1) receptors. The response to the M-2 receptor agonist , carbachol (0.01-3 mu M), was augmented to a comparable extent (Delta L, - 22%, dL/dt(max), -39%; P<0.01). Conclusions: In CHF, the inotropic response s to beta-receptor-stimulation and to direct stimulation of adenylyl cyclas e, but not to Ca2+, are diminished due to desensitisation of the stimulator y side of the adenylyl cyclase signal transduction system. In parallel, the responses to inhibitory receptors are augmented, leading to a pronounced G (i)-mediated negative inotropic effect on failing heart muscle cells. Those anti-adrenergic effects could contribute to the contractile dysfunction of the failing heart. Reversal of the sensitisation to inhibitory stimuli mig ht be one of the desirable mechanisms of medical therapy in CHF. (C) 1999 E lsevier Science B.V. All rights reserved.