Abstract 1220: Sildenafil Mediated Neovascularization Leads To Cardioprotection In Rat in vivo Myocardial Ischemia Reperfusion Model: Role Of VEGF And Ang-1
Sildenafil Citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Recent studies suggest that SC exerts antihypertensive, antithrombotic and cardioprotective effects through NO-cGMP pathway. The release of NO plays a critical role in angiogenic action. Our study aimed to determine a novel role of SC on cardioprotection through stimulating angiogenesis at both capillary and arteriolar levels and to examine the role of VEGF and Ang-1 in this mechanistic effect. We also investigated the functional relevance of such treatment by assessing the degree of neovascularization and left ventricular contractile reserve (LVCR) along with regional blood flow (RBF) by neutron microsphere technique during ischemia reperfusion (IR) injury. Rats were divided into 4 groups: Control sham, SC sham, Control+IR and SC+ IR. Rats were given 0.7 mg/kg i.v, SC or saline 30 min before occlusion of left anterior descending artery followed by 1, 2, 4 and 7 days of reperfusion (R). Immunohistochemical analysis demonstrated increased capillary density and arteriolar density in SC treated rats followed by increased RBF (2 fold) compared to controls. SC treatment demonstrated increased VEGF and Ang-1 mRNA after 6, 12 and 24hrs of reperfusion, however as expected Ang-2 mRNA was reduced gradually after 6hrs of R. Real time PCR data was validated by Western blot analysis after 2, 4 and 7 days of R. Significant reduction in infarct size (39% vs 20%) and cardiomyocyte apoptosis (304 vs 56) were observed after day 1. Increased expression of eNOS (5fold), anti-apoptotic protein Bcl2 (2fold) and redox-regulated protein, thioredoxin (2.5fold) were observed in SC treated rats. Echocardiography demonstrated significant increased fractional shortening and ejection fraction following 3 weeks of reperfusion in SC treated rats compared to corresponding controls. Stress testing with dobutamine infusion at 5 micro gm/kg/min revealed significant difference in the extent of LVCR between SC treated and controls. In conclusion, our study demonstrated a strong additional therapeutic potential of SC by upregulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.