imidapril and Cardiomyopathies

To explore the mechanisms of myocardial hypertrophy induced by Levothyroxine (L-Thy).. A rabbit model of hyperthyroidism was established by daily intraperitoneal injections of L-Thy (45 microg/kg per day) for 28 days. New Zealand rabbits were randomly divided into four groups (n = 10 each): control group, L-Thy group (L-Thy alone), imidapril group (L-Thy + 0.5 mg/kg imidapril), and valsartan group (L-Thy + 8 mg/kg valsartan). All rabbits were treated for 4 weeks. At the end of the treatments, all rabbits underwent echocardiography and IVS, LV and LVPW thickness were measured. Ventricular tissues were then collected.Cardiac hypertrophy index, cardiomyocyte diameter, structural and ultrastructural changes were obtained. Ventricular myocytes were isolated by enzymatic digestion method and intracellular Ca2+ concentration was determined with the fluorescent Ca2+ indicator Fluo3/AM and laser scanning confocal microscopy. Activity of Sarco/Endoplasmic reticulum Ca2+ ATPase (SERCA) was evaluated with P-NPP method.mRNA expression of L-type Ca2+ channel (LCC), ryanodine receptor (RyR), and SERCA was semi-quantified with RT-PCR. Protein of IP3R was localized by immunostaining and semi-quantified with pathological image analytic system.. Compared with control group, rabbits treated with L-Thy displayed remarkable myocardial hypertrophy and morphological changes in both structure and ultrastructure levels. Increased intracellular Ca2+ concentration [(576.2 +/- 41.7) nmol/L vs. (314.6 +/- 35.6) nmol/L, P < 0.01] and decreased SERCA activity [(0.062 +/- 0.013) micromol x min(-1)xg(-1) vs. (0.133 +/- 0.022) micromol x min(-1)xg(-1), P < 0.01] were detected in L-Thy treated rabbits. RT-PCR analysis and (or) immunohistochemistry revealed decreased mRNA expression of LCC mRNA (0.48 +/- 0.11 vs. 0.75 +/- 0.16, P < 0.01) and increased RyR mRNA (1.19 +/- 0.21 vs. 0.73 +/- 0.15, P < 0.01), SERCA mRNA (1.01 +/- 0.08 vs. 0.76 +/- 0.09, P < 0.01) and IP3R protein (65.3 +/- 13.7 vs. 47.9 +/- 10.2, P < 0.01) expression in L-Thy treated rabbits. Both imidapril and valsartan could significantly attenuate cardiomyocyte hypertrophy and structural remodeling induced by L-Thy. Compared with L-Thy group, decreased intracellular Ca(2+) concentration [(376.4 +/- 32.5) nmol/L vs. (576.2 +/- 41.7) nmol/L, P < 0.01 and (392.6 +/- 41.2) nmol/L vs. (576.2 +/- 41.7) nmol/L, P < 0.01, respectively], and increased LCC mRNA (0.68 +/- 0.14 vs. 0.48 +/- 0.11, P < 0.01; 0.64 +/- 0.13 vs. 0.48 +/- 0.11, P < 0.01, respectively) and SERCA activity [(0.115 +/- 0.019) micromol x min(-1)xg(-1) vs. (0.062 +/- 0.013) micromol x min(-1)xg(-1), P < 0.01; (0.109 +/- 0.015) micromol x min(-1)xg(-1) vs. (0.062 +/- 0.013) micromol x min(-1)xg(-1), P < 0.01, respectively] were found in both imidapril and valsartan treated rabbits, but expression of RyR, SERCA and IP3R remained unchanged.. Intracellular Ca(2+) overload may play important roles in myocardial hypertrophy induced by L-Thy. Imidapril and valsartan may exert beneficial effects on hyperthyroid myocardial hypertrophy via altering intracellular calcium handling.

Topics: Animals; Calcium; Calcium Channels; Cardiomyopathies; Disease Models, Animal; Hyperthyroidism; Imidazolidines; Myocardium; Rabbits; Renin-Angiotensin System; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tetrazoles; Thyroxine; Valine; Valsartan

We studied the effect of imidapril, a novel angiotensin-converting enzyme (ACE) inhibitor, on lifespan expectancy of cardiomyopathic (CM) hamsters of BIO 14.6 strain, one of the representative models of congestive heart failure (CHF). Imidapril was consecutively administered to hamsters by mixing it in their diet at a concentration of 480 ppm (approximately 30 mg/kg/day) or 1,600 ppm (approximately 120 mg/kg/day) from age 26 weeks. Only several control hamsters died before age 54 weeks, but their survival rate decreased to 23.7% at age 73 weeks. The survival rates of 480-ppm and 1,600-ppm imidapril groups at age 73 weeks were as high as 75.7 and 68.4%, respectively (p < 0.01 vs. control hamsters). Macroscopic and microscopic pathology in imidapril-treated groups was milder than that in control animals in general, but differences were not statistically significant when animals were divided into survivors and fatalities except for the presence of mural thrombus in the heart. We further studied the effects of imidapril on blood pressure (BP), in vivo cardiac function, cardiac beta-adrenoceptor distribution, and plasma catecholamine levels after dietary treatment with 480 ppm imidapril for 8-10 weeks from age 37 weeks. Imidapril-treated animals showed improved cardiac function under urethane anesthesia. These results indicate that imidapril prolongs lifespan expectancy of CM hamsters and suggest that a hemodynamic effect of imidapril is involved in its beneficial effect.

Topics: Adrenergic beta-Agonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathies; Cricetinae; Dopamine; Epinephrine; Ethanolamines; Hemodynamics; Imidazoles; Imidazolidines; Life Expectancy; Liver; Male; Myocardium; Norepinephrine; Receptors, Adrenergic, beta; Survival Rate