Sildenafil reduces<scp>L</scp>-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in the rat

Background and purpose: Phosphodiesterase-5 inhibitors are beneficial in pulmonary hypertension and congestive heart failure, the two conditions associated with coronary heart disease and ischaemia. We investigated whether sildenafil counteracts the cardiovascular alterations induced by Nω-nitro-L-arginine methyl ester (L-NAME) in the rat. Experimental approach: Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5 mg kg−1day−1 for four weeks, either alone or with L-NAME (35-40 mg kg−1 day−1 in the drinking water). Systolic blood pressure and urinary parameters (6-keto-prostaglandin F1α, thromboxane B2, 8-isoprostane-prostaglandin F2α and nitrite/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia–reperfusion, and myocardial levels of guanosine 3′, 5′cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings. Key results: Sildenafil dose-dependently prevented the rise in systolic blood pressure in L-NAME-treated rats. This activity was associated with a normalization of urinary 8-isoprostane-prostaglandin F2α and other biochemical parameters. In perfused hearts, the post-ischaemic ventricular dysfunction was worse in preparations from L-NAME-treated rats than in controls. Sildenafil dose-dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from L-NAME-treated rats, were restored by sildenafil. In noradrenaline-precontracted aortic rings from L-NAME-treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it. Conclusion and implications: In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post-ischaemic ventricular dysfunction are associated with loss of vascular endothelium-relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels. British Journal of Pharmacology (2007) 150, 567–576. doi:10.1038/sj.bjp.0707131