Effects Of DSP And Combination Use Of DSP And Fosinopril On Apoptosis In Left Ventricular Remodeling Of Spontaneously Hypertensive Rats

Objective This study was to investigate effects of combination use of DSP and fosinopril on apoptosis in left ventricular remodeling of Spontaneously Hypertensive Rats.Methods 48 eight-week-old male Spontaneously Hypertensive Rats (SHRs) were assigned randomly into six groups: group small dose DSP (SHRds); group large dose DSP (SHRdl); group fosinopril (SHRf); group combination use of small dose DSP and fosinopril (SHRds+f); group combination use of large dose DSP and fosinopril (SHRdl+f) and group placebo with distilled water (SHRc). Drugs and distilled water were given to each group of rats for 8 weeks and samples were taken at 16 weeks of age. Arterial systolic blood pressure (SBP) and left ventricular hypertrophy index (LVHI) were measured. Angiotensin â…¡(Angâ…¡) and aldosterone (Ald) were detected by radioimmunoassay. Expression of bcl-2 and bax protein were examined by immunohistochemistry. Cardiomyocyte apoptosis index of left ventricle (LV) of SHR was assessed by TUNEL. Ventricular fibrosis in SHR were evaluated according to collagen volume fraction (CVF) and perivasular circumferentiall area (PVCA). Ultrastructural features of left ventricular were observed by transmission electron microscope (ECM).Results 1. SBP was significantly lower in group SHRf, SHRds+f, SHRdl+f than that in group SHRc(P<0.01), while there was no apparently statistic significance between the SBP of groups SHRds, SHRdl and that of SHRc with the 4-week-treatment (P>0.05); SBP of groups DSP(SHRds, SHRdl) were significantly lower than SHRc after 8 weeks treatment(P<0.01), but the anti-hypertensive effects of DSP alone were less than that of group fosinopril and combination use of 2 drugs(P<0.01).2. LVHI was decreased in every treatment group. Combination use of 2 drugs was much more than the single use of fosinopril (P<0.01). DSP decreased the concentration of plasma Angâ…¡ and Ald and the concentration of Angâ…¡ of myocardium and could enhance the same effect of fosinopril (P<0.01 or P<0.05).3. Compared with SHRc, bcl-2 protein positive expression increased and bax protein positive expression decreaced after treatment. The ratio of bcl-2/bax increased significantly(P<0.01 or P<0.05), and apoptosis index (AI) decreased(P<0.01 or P<0.05 ). 4. Compared with SHRc, PVCA and CVF of endocardium and epicardium were decreased significantly in every treatment group (P<0.01)and the effect of combination use of large dose DSP and fosinopril was better than that of the single use of DSP or fosinopril(P<0.01 or P<0.05 ). 5. By ECM, ultrastructural features of left ventricle were observed. Compared with SHRc, ultrastructural features of left ventricle in every treatment group showed myocardial cell of uniform size with no apoptosis, well-arranged myofilament and intercalated disc, and the dramatically amelioration in interstitial fibrosis and congestion of blood capillary with edema of endothelial cell. Conclusion1. DSP has positive effect on the inhibition of the development of hypertension of SHR ,but doesn't lower SBP of SHR in short period.2. DSP can increase the ratio of bcl-2/bax and lower the myocardial apoptosis index. It can enhance the anti-apoptotic effect of myocardial cells of fosinopril by combination use of fosinopril and DSP.3. The mechanism of anti-apoptosis effect to myocardial cells by combination use of DSP and fosinopril may be associated with the effect of lowering the concentration of plasma Angâ…¡ and Ald and the concentration of Angâ…¡ of myocardium.4. DSP and Combination use of DSP and fosinopril can prevent left ventricular fibrosis in SHR while they decrease myocardial cell apoptosis and left ventricular hypertrophy of SHR.