BETA-1-RECEPTORS AND BETA-2-RECEPTORS ARE DIFFERENTIALLY DESENSITIZED IN AN EXPERIMENTAL-MODEL OF HEART-FAILURE

Recent reports suggested that a complex alteration in β-receptor function occurs in failing human myocardium. We evaluated β-receptor-subtype activity in an experimental model of monocrotaline (MCT)-induced cardiomyopathy in the rat. Through pulmonary hypertension, MCT causes right ventricular hypertrophy (RVH), either associated with heart failure or not. β-Receptor function was evaluated in both failing-hypertrophic and hypertrophic hearts in binding studies with [125]iodocyanopindolol (ICYP) and by measuring adenylate cyclase (AC) activity. In the right failing ventricle, β1- but not β2-receptor density was decreased. Lesion-associated modifications in the adenylate cyclase system were also observed: isoproterenol- and guanosine 5' [β,γ-imido]triphosphate [Gpp(NH)p]-stimulated cyclic AMP formation was reduced in the right failing ventricle, while the cyclic AMP responses to NaF and forskolin were unchanged. On the other hand, no changes in either β-receptor density or function were found in hypertrophic ventricles. MCT-induced heart failure in the rat is thus associated with a selective decrease of β1-receptor density and function. These results suggest that MCT-induced cardiac failure may be an appropriate model in which to investigate heart insufficiency futher.