Key result
Sildenafil prevents systolic hypertension but worsens post-ischemic dysfunction in nitric oxide-deficient rats.
Why the study?
Phosphodiesterase-5 inhibitors may benefit cardiovascular alterations associated with nitric oxide deprivation, hypertension, and ischaemia, but their effects in this context were not fully understood.
Does sildenafil reduce L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in rats?
Does sildenafil reduce L-NAME-induced severe hypertension and worsening of myocardial ischaemia-reperfusion damage in rats?
Sildenafil provides cardiovascular protection by maintaining tissue cGMP levels in a rat model of chronic nitric oxide deprivation, preventing hypertension and post-ischaemic ventricular dysfunction.
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 N ω‐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
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Rossoni et al. (2007) studied L-NAME-induced hypertension and myocardial ischaemia-reperfusion damage. Sildenafil vs. L-NAME alone / untreated controls was evaluated on Systolic blood pressure and post-ischaemic ventricular dysfunction. Sildenafil dose-dependently prevented the rise in systolic blood pressure and worsened post-ischaemic ventricular dysfunction in a rat model of chronic nitric oxide deprivation.
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