Role of Neurohumoral Abnormalities and -Adrenergic Reeptor Changes in Progression of Chronic Heart Failure

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It is well known that inotropic response of the beta-adrenoceptor stimulation is markedly depressed in congestive heart failure. This phenomenon is due to the down-regulation of beta-adrenergic receptors and abnormalities of the subcellular signal transduction system. However, in the pre-failure stage, cardiac beta-adrenoceptors are often increased. These observations may support the view that beta-adrenoceptor changes play an important role in manifestation of the heart failure. To test this hypothesis, we studied the changes in cardiac function and beta-adrenoceptor density in dogs 7 days after recovery from acute myocardial ischemia produced by intracoronary microembolization (15 or 25 m in diam). Myocardial norepinephrine content was depleted, but the number of betaadrenergic receptors was increased, and thus basal cardiac function was restored to normal. However, inotropic response to intravenous administration of forskolin was significantly depressed whereas the response to isoproterenol was apparently normal. These results indicate that an increase in beta-adrenergic receptors in ischemic cardiomyopathy may compensate the impaired subcellular signal transduction of beta-receptors. To verify this idea, increased beta-adrenergic receptors were imposed to be down-regulated by sustained infusion of isoproterenol. As expected, overt heart failure became manifest following the down-regulation of betaadrenoceptors. These results indicate that beta-adrenoceptor change plays a major role in compensation and expression of heart failure.