Sildenafil reduces aortic endothelial dysfunction and structural damage in spontaneously hypertensive rats: Role of NO, NADPH and COX-1 pathways.
Arterial hypertension is a condition associated with endothelial dysfunction, accompanied by an imbalance in the production of reactive oxygen species (ROS) and NO. The aim of this study was to investigate and elucidate the possible mechanisms of sildenafil, a selective phosphodiesterase-5 inhibitor, actions on endothelial function in aortas from spontaneously hypertensive rats (SHR). SHR treated with sildenafil (40 mg/kg/day, p.o., 3 weeks) were compared to untreated SHR and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and vascular reactivity was determined in isolated rat aortic rings. Circulating endothelial progenitor cells and systemic ROS were measured by flow cytometry. Plasmatic total antioxidant capacity, NO production and aorta lipid peroxidation were determined by spectrophotometry. Scanning electron microscopy was used for structural analysis of the endothelial surface. Sildenafil reduced high SBP and partially restored the vasodilator response to acetylcholine and sodium nitroprusside in SHR aortic rings. Using selective inhibitors, our experiments revealed an augmented participation of NO, with a simultaneous decrease of oxidative stress and of cyclooxygenase-1 (COX-1)-derived prostanoids contribution in the endothelium-dependent vasodilation in sildenafil-treated SHR compared to non-treated SHR. Also, the relaxant responses to sildenafil and 8-Br-cGMP were normalized in sildenafil-treated SHR and sildenafil restored the pro-oxidant/antioxidant balance and the endothelial architecture. In conclusion, sildenafil reverses endothelial dysfunction in SHR by improving vascular relaxation to acetylcholine with increased NO bioavailability, reducing the oxidative stress and COX-1 prostanoids, and improving cGMP/PKG signaling. Also, sildenafil reduces structural endothelial damage. Thus, sildenafil is a promising novel pharmacologic strategy to treat endothelial dysfunction in hypertensive states reinforcing its potential role as adjuvant in the pharmacotherapy of cardiovascular diseases.
['Leal|Marcos A S|MAS|', 'Aires|Rafaela|R|', 'Pandolfi|Thamirys|T|', 'Marques|Vinicius Bermond|VB|', 'Campagnaro|Bianca Prandi|BP|', 'Pereira|Thiago M C|TMC|', 'Meyrelles|Silvana S|SS|', 'Campos-Toimil|Manuel|M|', 'Vasquez|Elisardo C|EC|']
D000818:Animals D000959:Antihypertensive Agents D001011:Aorta D001794:Blood Pressure D006152:Cyclic GMP D051545:Cyclooxygenase 1 D004195:Disease Models, Animal D066026:Endothelial Progenitor Cells D004730:Endothelium, Vascular D006973:Hypertension D015227:Lipid Peroxidation D008297:Male D008565:Membrane Proteins D009249:NADP D009569:Nitric Oxide D018384:Oxidative Stress D058986:Phosphodiesterase 5 Inhibitors D011918:Rats, Inbred SHR D011921:Rats, Inbred WKY D015398:Signal Transduction D000068677:Sildenafil Citrate D014664:Vasodilation D014665:Vasodilator Agents
Sildenafil Endothelial dysfunction Hypertension Spontaneously hypertensive rats (SHR) Oxidative stress cGMP GMP-dependent protein kinase (PKG) Nitric oxide PDE5