Combined effects of ramipril and angiotensin Ⅱ receptor blocker TCV116 on rat congestive heart failure after myocardial infarction

Background Congestive heart failure (CHF) is a majo r cause of morbidity and mortality worldwide and angiotensin converting enzyme inhibitor (ACEI) is the cornerstone in its treatment However, CHF continues to progress despite this therapy, perhaps because of production of angiotensin Ⅱ (Ang Ⅱ) by alternative pathways The present study was conducted to examine th e combined effects of a chronic ACEI, ramipril, and a chronic Ang Ⅱ type 1 rece ptor blocker, TCV116, on rat CHF after myocardial infarction (MI) Methods Congestive heart failure was caused by MI in rats, whic h wa s induced by ligating the left anterior descending coronary artery The experiment protocol included sham operated rats (Sham), MI control rats (MI control), MI rats treated with ramipril 3 mg/kg (MI ramipril) or TCV116 2 mg/ kg (MI TCV116) per day, half dosage (MI 1/2R&T) or full dosage (MI R&T) combi n ation of the two At 22 weeks, cardiac hemodynamic parameters such as mean arte rial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate of left ventricule pressure development and decline (LV dP/dtmax) and left ve ntricular end diastolic pressure (LVEDP), and cardiac morphometric parameters su ch as heart weight (HW), left ventricular weight (LVW) and left ventricular cavi ty area (LVCA) were measured, mRNA expressions of cardiac molecule genes such as β myosin heavy chain (βMHC), B type natriuretic peptide (BNP), transforming growth factor β1 (TGF β1), collagen I and Ⅲ were quantified with rever se t ranscription polymerase chain reaction (RT PCR) in the surviving septum myocard ium, and survival rates were calculated Results There were no significant differences in MI sizes ( %) among each MI related experimental groups (33±13, 34±14, 33±13, 35±13 and 33±14 for MI control, MI ramipril, MI TCV116, MI 1/2R&T and MI R&T, resp e ctively, no statistical significance for all) Compared with sham operated rat s, MI rats without therapy showed significant increases in morphometric paramete rs as well as in mRNA expressions of cardiac molecule genes (P<001); while their hemodynamic parameters were significantly impaired (P<001), and in terms of spontaneous deaths survival rate shortened (P<005) Compared wit h MI rats without therapy, MI rats treated with each single drug showed sign ific ant attenuation of mRNA expressions of cardiac molecule genes (P<001); whi le their hemodynamic parameters were significantly improved (P<005 or P <001), and in terms of spontaneous deaths survival rate prolonged (P<0 05) Both half and full dosage combined treatments exerted more powerful effect s on improvement of cardiac phenotypic changes and on attenuation of βMHC, BNP mRNA expressions (P<005 vs monotherapy); while LVEDP was further lowered ( P<005 vs monotherapy) However, the total death in MI rats with full dosa ge combined treatment was more though there were no significant differences when compared with other treatments Conclusions The results suggest that treatment with appropri ate dosage combination of a chronic ACEI and a chronic ARB may further improve c ardiac remodeling and cardiac function after MI