Effects of propranolol treatment on left ventricular function and intracellular calcium regulation in rats with postinfarction heart failure

Abstract

1. Chronic treatment with beta-adrenergic blocking agents can improve survival in patients with heart failure. The mechanisms underlying the beneficial effects and whether these effects are generalizable to ischaemic heart failure are unresolved. 2. We performed echocardiographic-Doppler examinations in rats (n=28) 1 and 6 weeks after myocardial infarction (MI) or sham surgery. Rats were randomized to no treatment or propranolol (500 mg/l in drinking water) after the first echocardiogram. Isometric contractions and intracellular Ca transients were recorded simultaneously in noninfarcted left ventricular (LV) papillary muscles. 3. Untreated MI rats had significant LV dilatation (10.6+/-0.4* vs 8.9+/(-0.3) mm, MI vs control), impaired systolic function (fractional shortening=11+/-2* vs 38+/-2%), and a restrictive LV diastolic filling pattern. MI rats receiving propranolol had similar LV chamber sizes (10.6+/(-0.5) mm) and systolic function (13+/(-2%). The propranolol treated animals had higher LV end-diastolic pressures (27+/-2* vs 20+/(-3 mmHg) and a more restricted LV diastolic filling pattern (increased ratio of early to late filling velocities and more rapid E wave deceleration rate). Contractility of papillary muscles from untreated MI rats was depressed (1.6+/(-0.3) vs 2.4+/(0.5 g mm(-2). In addition, Ca transients were prolonged and the inotropic response to isoproterenol was blunted. Propranolol treatment did not improve force development (1.6+/(-0.3 g mm(-2) or the duration of Ca transients during isoproterenol stimulation. 4. Chronic propranolol treatment in rats with postinfarction heart failure did not improve LV remodeling or systolic function. LV diastolic pressures and filling patterns were worsened by propranolol. Treatment also did not produce appreciable improvement in contractility, intracellular Ca regulation or beta-adrenergic responsiveness in the noninfarcted myocardium.

Figure 1

Time course of echocardiographically assessed changes in left ventricular (LV) geometry and systolic function in rats after transmural anterior wall myocardial infarction (MI; n=14) or sham surgery (n=14). Immediately following the 1 week echocardiogram, rats from each group were randomized to propranodol (500 mg l⁻¹ in the drinking water) or no treatment. Treatment was continued for 5 weeks. (A) Rats with MI showed prominent pathological LV remodelling manifest as increased LV internal diastolic dimension. The extent of LV dilatation was not significantly altered by chronic propranodol treatment. MI caused marked and progressive LV systolic dysfunction as shown by increased LV end-systolic dimension (B) and decreased fractional shortening (C). These changes were not prevented by the administration of propranodol. ^*P<0.005 vs sham. Propranodol MI vs untreated MI=NS.

Figure 2

Changes in left ventricular (LV) diastolic filling in sham operated rats and rats with myocardial infarction (MI) randomized to propranodol or no treatment. Untreated MI rats developed restrictive LV filling patterns as assessed by (A) the ratio of early to late filling velocities (E/A), (B) the E wave deceleration slope, and (C) the isovolumic relaxation time. Propranodol treatment significantly worsened the E to A ratio in MI rats, tended to cause further increases in the E wave deceleration rate, and did not change the isovolumic relaxation time. ^*P<0.05 vs sham operated rats. †P<0.05 propranodol MI vs untreated MI.

Figure 3

Response to increasing isoproterenol concentration in papillary muscles from sham operated rats and rats with postinfection heart failure randomized to no treatment or propranodol. Papillary muscles from myocardial infarction (MI) rats had lower peak rate of tension rise (A) at all isoproterenol concentrations. Propanolol treatment did not improve the blunted inotropic response to isoproterenol in the papillary muscle from infarcted hearts. (B) Although the MI papillary muscles had prolongation of the isometric twitch at baseline, isoproterenol significantly shortened the time to peak tension. This effect was similar in muscles from untreated and propranodol treated rats. The time course of the intracellular Ca transient was also prolonged in papillary muscles from infarcted hearts (C and D). Again, the muscles from propranodol treated MI rats responded similarly to those from the untreated MI rats. Data are mean±s.e.mean. ^*P<0.05 vs sham. Propranodol MI vs untreated MI=NS.