Effects of losartan, ramipril and their combination on left ventricular remodeling and function in spontaneous hypertensive rats

Abstract

To evaluate the effects of losartan, an angiotensin receptor blocker, ramipril, an angiotensin converting enzyme inhibitor, and their combination on left ventricular remodeling and diastolic function in SHR at the same level of blood pressure. Sixty-two SHRs and 20 WKYs were divided randomly into 5 groups: WKY-control group, SHR-control group, SHR-ramipril group, SHR-losartan group, and SHR-combination group. Twelve weeks after feeding, 6 rats from each group were randomly selected to undergo hemodynamic examination and then killed to undergo further examinations, and 24 weeks after the remaining rats underwent the same examinations. The hemodynamic examination included the systolic blood pressure (SBP) of the caudal artery, left ventricular systolic pressure (LVSP), left ventricle end diastolic pressure (LVEDP), maximum uprising velocity of left ventricle pressure (dP/dtmax), and maximum declining velocity of left ventricle pressure (-dP/dtmax), and tau. Then the hearts were taken out to measure the weight of heart, undergo pathological examination, measure the intracellular free calcium concentrations, hydroxyproline concentration, interstitial collagen volume fraction (CVF), perivascular collagen area/luminal area (PVCA/LA), the mRNA expression of SR Ca(2+)-ATPase, phospholamban and L-type calcium channel, and the protein levels of SR Ca(2+)-ATPase. The myocardial ultrastructure was analyzed by electron microscopy. The speed, extent, and sustained time of blood pressure decrease were better in the combination group than in the other 2 treatment groups. Twelve and 24 weeks after treatment the levels of LVM/BW in the combination group were significantly lower than those of the control group, however, without significant differences among the 3 treatment groups. The values of LVSP, LVEDP, and tau 12 and 24 weeks after treatment in the 3 treatment groups were all significantly lower and the levels of -dP/dtmax significantly higher than those of the control group (all P < 0.01). The values of CVF in the myocardium and PCVA/VA of the heart wall arteriole 12 and 24 weeks after in the 3 treatment groups were significantly lower than those of the control group, and the CVF in the myocardium 12 weeks after in the combination group was significantly than that of the ramipril group. Microscopy showed that the degree of myocardial fibrosis in the 3 treatment groups were significantly milder than those of the control group, and the ultrastructure improvement improved along with the lapse of time in the sequence of combination group > losartan group > ramipril group. The concentrations of hydroxyproline in cardiac muscle cells of the 3 treatment 12 and 24 weeks after were significantly than those of the control group and decreased gradually time-dependently. The expression of Ca(2+)-ATPase mRNA 24 weeks after of the ramipril, losartan, and combination groups were 53.5%, 72.9%, and 76.7% higher than that of the control group, and the Ca(2+)-ATPase protein expression of the 3 treatment groups were 28.9%, 33.3%, and 49.3% higher than that of the control group. The expression of L-type Ca(2+) channel mRNA of the 3 treatment groups were 51.8%, 76.8%, and 98.2% than that of the control group. Both losartan and ramipril reverse LVH and left ventricular diastolic dysfunction. A combination of these two drugs is more effective than single drug treatment for improvement of myocardial fibrosis and ultrastructure. All three-treatment groups can raise calcium-handling proteins mRNA and protein expressions, which may be the underlying molecular mechanisms for their therapeutic effects.