MYOCARDIAL BETA-ADRENERGIC-RECEPTOR EXPRESSION AND SIGNAL TRANSDUCTION AFTER CHRONIC VOLUME-OVERLOAD HYPERTROPHY AND CIRCULATORY CONGESTION

Background. The volume-overload, high-output state induced by aortocaval fistula is unique because it is not generally associated with marked abnormalities of contractile function. Thus, changes in beta-adrenergic receptor (beta-AR) expression should reflect more directly the influence of neurohumoral adrenergic tone, clarifying the manner in which peripheral (neurohumoral) versus primary myocardial factors are operative in decreased beta-AR-dependent signal transduction. Methods and Results. We examined the beta-adrenergic receptor-responsive adenylyl cyclase pathway in hearts from pigs subjected to volume-overload hypertrophy with circulatory congestion. Nine pigs underwent initial pharmacological and hemodynamic studies, and, 5 weeks after aortocaval fistula placement, when signs of circulatory congestion were evident, these measurements were repeated. Biochemical analyses of plasma and myocardium from these animals and seven normal animals were compared. Experimental animals showed signs of circulatory congestion (tachypnea, weight gain, pulmonary rales) within 3-4 weeks of fistula placement. Necropsy showed ascites and biventricular cardiac hypertrophy, but no fibrosis or inflammation was present on histological inspection. Heart rate responsiveness to beta-AR stimulation was blunted, with ED50, for isoproternol increased 133% (p < 0.001) after development of circulatory congestion. Biochemical analyses of the beta-AR-responsive adenylyl cyclase pathway showed uniform decreases in beta-AR number in right atrium, right ventricle, and left ventricle (36-41% decreases, p < 0.005). Downregulation was selective for beta(1)-receptors, and remaining receptors in the right and left ventricles showed low-affinity agonist binding, suggesting an uncoupling from G(S). All measures of adenylyl cyclase activity were diminished significantly in membrane homogenates from the right atrium (mean reduction, 50 +/- 10%) and left ventricle (mean reduction, 44 +/- 8%) after volume overload. Finally, we found that amounts of cardiac G(S), as measured in reconstitution assays, were decreased in both the right atrium (p < 0.02) and the left ventricle (p < 0.01) of volume-overloaded animals but that levels of pertussis toxin substrate were unchanged. Conclusions. Biochemical findings occurred in the absence of myocardial inflammation or fibrosis and without pharmacological interventions, suggesting that circulatory congestion, with attendant elevation in plasma norepinephrine, may be a sufficient stimulus to induce such changes. The data are compatible with a catecholamine-driven beta-AR pathway desensitization. Thus, a primary defect in intrinsic contractile function is not a necessary component for abnormalities of the myocardial beta-AR-responsive adenylyl cyclase pathway.