Mitigation of beta 1- and/or beta 2-adrenoceptor function in human heart failure

1. Patients with congestive heart failure (CHF) have an elevated activity of the sympatho-adrenal system. We have investigated several aspects of beta-adrenoceptor desensitization in such patients. 2. The positive inotropic response to isoprenaline was attenuated in CHF patients, and the pD2-values for isoprenaline's positive inotropic effect gradually decreased in more severe forms of the disease. Stimulation of adenylate cyclase by isoprenaline was also mitigated in cardiac membranes from patients with CHF. 3. We then studied the density of cardiac beta 1- and beta 2-adrenoceptors in order to understand the mechanism of beta-adrenoceptor desensitization in these patients. Our data show that cardiac beta 1-adrenoceptors are down-regulated in all forms of severe CHF, but that cardiac beta 2-adrenoceptor density decreases only in some forms of CHF including ischaemic cardiomyopathy and mitral valve disease. 4. In circulating mononuclear leucocytes (MNL) obtained from CHF patients at rest, isoprenaline- and prostaglandin E1-stimulated cAMP generation as well as cholera toxin and pertussis toxin catalyzed ADP ribosylation were similar to those in MNL from control patients. However, pretreatment of intact MNL with pertussis toxin enhanced cAMP generation in CHF patients but not in healthy control subjects, suggesting a tonic inhibitory effect of Gi in such patients. 5. We conclude that alterations of adrenoceptors and of their signal transduction might contribute to the desensitization of beta-adrenergic responses in CHF.