Juan Wen

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.

Comparative effects of pranidipine with amlodipine in rats with heart failure.

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and ±dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-α, and improved sarcoplasmic reticulum Ca2+ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

Comparative Effects of Quinapril with Enalapril in Rats with Heart Failure

The cardioprotective properties of angiotensin-converting enzyme (ACE) inhibitors, quinapril and enalapril were studied in a rat model of heart failure. Seventy-five rats were divided into five groups and administered quinapril or enalapril at 2 and 20 mg/kg/day (groups Q2, Q20, E2 and E20) or vehicle alone (group V, all groups n = 15). Although both ACE inhibitors improved survival rate and ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and expression level of transforming growth factor-β1 mRNA were the lowest in group Q20. These results suggest that quinapril may confer greater protection than enalapril against injury from the renin-angiotensin system in heart failure.

Effect of carvedilol against myocardial injury due to ischemia–reperfusion of the brain in rats

We have previously reported the mechanism behind the myocardial injury and the activation of autonomic nervous system during the ischemia-reperfusion (IR) of the rat brain. This study was planned to investigate the effect of carvedilol, a β-blocker, in improving the myocardial injury caused by IR of the rat brain. We have used a whole cerebral IR model in rats by clamping both the right and left common carotid arteries. Rats were divided into five groups; Sham surgery group (Group-Sham), carvedilol treatment before ischemia group (Group-Is+C), vehicle control group (Group-Is+V), carvedilol treatment before reperfusion group (Group-Re+C) and the vehicle control group (Group-Re+V). We have measured the blood pressure and heart rate via a catheter, myocardial tissue β1-adrenaline receptor (β1-AR) levels, phosphor-p38 mitogen-activated protein kinase (p-p38 MAPK) signaling factor, malondialdehyde (MDA), and apoptosis (TUNEL assay and expression of caspase-7 protein). The results indicated that the increased expressions of β1-AR, p-p38 MAPK, caspase-7, apoptotic cells and MDA level in the myocardial tissue due to brain ischemia-reperfusion were significantly reduced by carvedilol treatment. From these observations we can suggest that, with the advantage of its antioxidant and β blocking action, carvedilol had played the improvement of myocardial injury in ischemia-reperfusion of the brain.

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.