Gurusamy Narasimman

Comparative Effects of Perindopril with Enalapril in Rats with Dilated Cardiomyopathy

Summary: Angiotensin‐converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type‐1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type‐1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty‐eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin‐converting enzyme inhibitors improved ventricular function in a dose‐dependent manner, the left ventricular end‐diastolic pressure and area of myocardial fibrosis were lower, and ± dP/dt was higher in Group P2 (4.9 ± 0.6 mmHg, 7.5 ± 1.4% and +2651 ± 254/ ‐2622 ± 189 mmHg/s, respectively) than in Group V (16.7 ± 1.3, 36 ± 2.6 and +2659 ± 176/‐2516 ± 205, respectively) and Group E20 (7.5 ± 2.5, 15.6 ± 2.0 and +2018 ± 110/‐2097 ± 102, respectively). Although the expression levels of transforming growth factor‐&bgr;1 and collagen‐III mRNA in Group V (36.3 ± 5.7 and 157.6 ± 12.7%) were significantly higher than those in Group N (19.6 ± 3.0 and 65.2 ± 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 ± 5.9 and 75.2 ± 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type‐1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin‐angiotensin system in heart failure.

Contribution of sympathetic nervous system activity during administration of carvedilol in rats with dilated cardiomyopathy.

Summary: We investigated the contribution of the sympathetic nervous system (SNS) in maintaining blood pressure during administration of carvedilol in rats with dilated cardiomyopathy, and examined whether SNS hyperactivity induced by high‐dose carvedilol is related to severity of heart failure. The hypotensive effect of carvedilol in rats with heart failure (Group F) was not significantly different to that in rats without (Group N). However, enhancement of the plasma norepinephrine concentration during carvedilol administration in Group F was higher than in Group N. The constitutive plasma NE concentration in Group F (562 ± 146 pg/ml) was significantly higher than in Group N (203 ± 55 pg/ml) and there was a significant positive correlation between the heart weight to body weight ratio and the plasma norepinephrine concentration. Values for the maximal effect of the norepinephrine hypertensive effect during norepinephrine intravenous infusion (Emax) decreased, and plasma norepinephrine concentrations at half‐maximal effect of the norepinephrine hypertensive effect (EC50) increased in Group F compared with Group N (20.8 ± 6.1 and 28.6 ± 2.2 mmHg, and 4.5 ± 1.9 and 1.5 ± 0.2 ng/ml, respectively). These results suggested that the number of receptors (Emax) and sensitivity (EC50) to the norepinephrine hypertensive effect decreased in Group F. Changes in these parameters in Group F corresponded with the results of a &bgr;‐adrenergic receptor binding assay using I‐125 iodocyanopindolol (Bmax = 32 ± 4 in Group F and 53 ± 2 fmol/mg protein in Group N). These results showed that the SNS (presynaptic) activity increased and the SNS receptor sensitivity in the blood pressure regulation system decreased in heart failure. Therefore, high‐dose carvedilol treatment should be used with caution to avoid worsening heart failure.

Hemodynamic effects of carvedilol infusion and the contribution of the sympathetic nervous system in rats with heart failure

We investigated the contribution of the sympathetic nervous system (SNS) in maintaining the blood pressure and in regulating the cardiac function during and after carvedilol administration in rats with heart failure (group F). Left ventricular end-diastolic pressure, percent functional shortening, and rates of intraventricular pressure rise were significantly changed by carvedilol infusion as compared with the basal values in group N (normal rats), but not in group F. The left ventricular end-diastolic pressure was elevated, corresponding to the enhancement of the plasma norepinephrine (NE) concentration caused by carvedilol infusion, in group N. The enhancement of the plasma NE concentration induced by carvedilol administration in group F was higher than that in group N. The value for the maximal hypertensive effect of NE intravenous infusion (Emax) was decreased, and the plasma NE concentration at half-maximal effect (EC50) was increased in group F as compared with the values in group N. These results indicate that the SNS (presynaptic) activity is increased and that the SNS receptor sensitivity in the cardiovascular regulation system is decreased in heart failure.