Sildenafil‐mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin‐1

Abstract

Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control + IR (CIR) and sildenafil + IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating 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.

Sildenafil Alleviates Bronchopulmonary Dysplasia in Neonatal Rats by Activating the Hypoxia-Inducible Factor Signaling Pathway

“…In particular, sildenafil was developed to mimic the pharmacological action of NO by increasing intracellular cyclic guanosine 39,59-monophosphate (cGMP) concentrations. Ladha and colleagues (19) demonstrated that sildenafil improves alveolar growth and ameliorates BPD-associated pulmonary hypertension in rats with BPD, and sildenafil was also reported to ameliorate BPD symptoms by augmenting the neovascularization mediated by VEGF and angiopoietin-1 (20). Currently, sildenafil is undergoing clinical trials as a BPD therapeutic regimen (21,22).…”

P6.11 Phosphodiesterase Type-5 Inhibitor Use in Type 2 Diabetes Is Associated With a Reduction in All Cause Mortality

“…9 This is supported by compelling evidence from animal models indicating that the PDE5is such as sildenafil, tadalafil and vardenafil are cardioprotective in ischaemia-reperfusion injury (IRI) while suppressing cardiac arrhythmias and improving cardiac function. [10][11][12][13][14][15] Furthermore, small randomised controlled trials (RCTs) in systolic heart failure have shown an improvement in haemodynamic parameters and functional indices. 16 It is therefore important to establish whether there is benefit or harm in highrisk patients with ED.…”

Micro-recanalization in a biodegradable graft for reconstruction of the vas deferens is enhanced by sildenafil citrate

“…Its mechanism of action involves inhibition of the breakdown of cyclic GMP, which in turn leads to local vasodilation. Recently, sildenafil has also been shown to increase expression of vascular endothelial growth factor and angiopoietin-1, leading to increased neovascularization in a rat model of coronary ischemia and promoting functional recovery after stroke in a rat model of cerebral ischemia [6,8].…”

“…cGMP has been implicated in post-natal angiogenesis. Sildenafil citrate leads to increased vascular endothelial growth factor expression and angiogenesis in a rat model of coronary ischemia [6]. In addition, administration of oral sildenafil citrate improved recovery of spontaneous 'normal' erections following radical prostatectomy in a controlled study [7].…”