Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial beta-adrenergic signaling.

Abstract

Patients with chronic heart failure frequently show blunted circadian blood pressure profiles. The mechanisms involved in the loss of physiological day-night variation are still unclear, but a continuously active sympathetic nervous system could play a role. The present study evaluated long-term consequences of rat heart failure on cardiovascular circadian patterns in vivo, and on density and function of cardiac beta-adrenoceptor subtypes in vitro, as a marker of cardiac adrenergic drive. Heart failure in rats was induced by coronary artery ligation leading to infarct sizes of >30% of left ventricular circumference. Blood pressure and heart rate were monitored for 10 weeks after infarction using radiotelemetry. Density and function of cardiac beta(1) and beta(2)-adrenoceptors were measured by radioligand binding and adenylyl cyclase stimulation. During the activity period at night blood pressure and heart rate were lower in rats with heart failure than in sham controls, leading to reduced night-day variation in the heart failure group. Depression of circadian rhythmicity in blood pressure was found over the whole study period, while that in heart rate occurred with a lag-time of several weeks. In failing left ventricles beta-adrenoceptors showed reduced high affinity agonist binding, a shift in the beta(1):beta(2) ratio towards the beta(2)-subtype, and decreased beta(1)-adrenergic stimulation of adenylyl cyclase. In right ventricles no differences were found between failing and control rats. The blunted nocturnal increase in blood pressure and heart rate as well as beta(1)-adrenergic desensitization were correlated with the severity of left ventricular dysfunction. Heart failure in rats leads to disturbed circadian patterns in blood pressure and heart rate, and to desensitization of cardiac beta(1)-adrenoceptors, indicating chronic sympathetic overactivity.