CAPTOPRIL ENHANCES INTRACELLULAR CALCIUM HANDLING AND BETA-ADRENERGIC RESPONSIVENESS OF MYOCARDIUM FROM RATS WITH POSTINFARCTION FAILURE

To examine the cellular mechanisms of contractile dysfunction in postinfarction heart failure, we studied the effects of beta-adrenergic receptor stimulation on contractile function and Ca2+i handling of noninfarcted papillary muscles from sham-operated (n=17) and infarcted (n=17) rats. Ca2+i transients measured with the bioluminescent protein aequorin and parameters of isometric contraction were recorded during graded isoproterenol stimulation. Developed tension and peak rate of tension rise were depressed (p<0.05) in muscles from infarcted rats at physiological and maximally stimulating [Ca2+](o)s. The time to peak tension was prolonged in the muscles from the infarcted rats, corresponding with prolongation of the time to peak Ca2+i. In muscles from sham-operated rats, isoproterenol increased both the amplitude of the Ca2+i transient and the peak rate of tension rise. In contrast, the inotropic response to isoproterenol was severely blunted in the muscles from infarcted rats despite a large increase in the amplitude of the Ca2+i transient. Isoproterenol abbreviated the time course of the isometric twitch and the Ca2+i transient in both groups. These findings suggest that postinfarction heart failure may be related in part to decreased force-generating capacity of the myofilaments. Treatment with captopril for 5 weeks, beginning 1 week after infarction (n=14), resulted in reduction of left ventricular filling pressures and partial normalization of myocardial contractility and Ca2+i handling. In addition, compared with muscles from untreated infarcted rats, muscles from the captopril-treated rats exhibited improved contractile responses to increasing [Ca2+]o or isoproterenol. The inotropic response to isoproterenol in muscles from all three groups of rats had a significant negative correlation (r= -0.64, p<0.0001) with left ventricular end-diastolic pressure measured in vivo. Thus, the defect in excitation-contraction coupling in rats with postinfarction heart failure may be partially normalized by chronic load reduction with an angiotensin converting enzyme inhibitor.