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 major 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 the combined effects of a chronic ACEI, ramipril, and a chronic Ang II type 1 receptor blocker, TCV116, on rat CHF after myocardial infarction (MI).


METHODS
Congestive heart failure was caused by MI in rats, which was 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) combination of the two. At 22 weeks, cardiac hemodynamic parameters such as mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), maximal rate of left ventricule pressure development and decline (LV dP/dtmax) and left ventricular end diastolic pressure (LVEDP), and cardiac morphometric parameters such as heart weight (HW), left ventricular weight (LVW) and left ventricular cavity area (LVCA) were measured, mRNA expressions of cardiac molecule genes such as beta myosin heavy chain (betaMHC), B-type natriuretic peptide (BNP), transforming growth factor-beta1 (TGF-beta1), collagen I and III were quantified with reverse transcription polymerase chain reaction (RT-PCR) in the surviving septum myocardium, 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, respectively, no statistical significance for all). Compared with sham-operated rats, MI rats without therapy showed significant increases in morphometric parameters 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 with MI rats without therapy, MI rats treated with each single drug showed significant attenuation of mRNA expressions of cardiac molecule genes (P < 0.01); while 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 effects on improvement of cardiac phenotypic changes and on attenuation of betaMHC, 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 dosage combined treatment was more though there were no significant differences when compared with other treatments.


CONCLUSIONS
The results suggest that treatment with appropriate dosage combination of a chronic ACEI and a chronic ARB may further improve cardiac remodeling and cardiac function after MI.
Tao
Ze-wei
ZW
Department of Cardiology, Chinese People Armed Police Force Hospital of Hunan Province, Changsha 410006, China. taozw@hotmail.com
Huang
Yuan-wei
YW
Xia
Qiang
Q
Xu
Qi-wen
QW
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000473:pathology; D017257:Ramipril / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D013777:Tetrazoles / Q000008:administration & dosage*; D016277:Ventricular Function, Left / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D017257:Ramipril; C077793:candesartan cilexetil