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We investigated whether sildenafil counteracts the cardiovascular alterations induced by <jats:italic>N<\/jats:italic>\n<jats:sup>\u03c9<\/jats:sup>\u2010nitro\u2010L\u2010arginine methyl ester (<jats:sc>L<\/jats:sc>\u2010NAME) in the rat.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Sildenafil was given orally to rats at doses of 0.37, 0.75 or 1.5\u2003mg kg<jats:sup>\u22121<\/jats:sup>day<jats:sup>\u22121<\/jats:sup> for four weeks, either alone or with <jats:sc>L<\/jats:sc>\u2010NAME (35\u201040\u2003mg kg<jats:sup>\u22121<\/jats:sup> day<jats:sup>\u22121<\/jats:sup> in the drinking water). Systolic blood pressure and urinary parameters (6\u2010keto\u2010prostaglandin F<jats:sub>1\u03b1<\/jats:sub>, thromboxane B<jats:sub>2<\/jats:sub>, 8\u2010isoprostane\u2010prostaglandin F<jats:sub>2\u03b1<\/jats:sub> and nitrite\/nitrate) were measured in conscious rats. Isolated hearts were subjected to low flow ischaemia\u2013reperfusion, and myocardial levels of guanosine 3\u2032, 5\u2032cyclic monophosphate (cGMP) were determined. Endothelial vascular dysfunction was examined in aortic rings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>Sildenafil dose\u2010dependently prevented the rise in systolic blood pressure in <jats:sc>L<\/jats:sc>\u2010NAME\u2010treated rats. This activity was associated with a normalization of urinary 8\u2010isoprostane\u2010prostaglandin F<jats:sub>2<jats:italic>\u03b1<\/jats:italic><\/jats:sub> and other biochemical parameters. In perfused hearts, the post\u2010ischaemic ventricular dysfunction was worse in preparations from <jats:sc>L<\/jats:sc>\u2010NAME\u2010treated rats than in controls. Sildenafil dose\u2010dependently reduced this effect, and creatine kinase and lactate dehydrogenase release were lower too. cGMP levels, which were low in myocardial tissue from <jats:sc>L<\/jats:sc>\u2010NAME\u2010treated rats, were restored by sildenafil. In noradrenaline\u2010precontracted aortic rings from <jats:sc>L<\/jats:sc>\u2010NAME\u2010treated rats acetylcholine lost its vasorelaxant effect, and sildenafil restored it.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications:<\/jats:title><jats:p>In a rat model of chronic nitric oxide deprivation, where hypertension and aggravation of post\u2010ischaemic ventricular dysfunction are associated with loss of vascular endothelium\u2010relaxant function, sildenafil provided significant cardiovascular protection, primarily by maintaining tissue cGMP levels.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2007) <jats:bold>150<\/jats:bold>, 567\u2013576. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0707131\">10.1038\/sj.bjp.0707131<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1038\/sj.bjp.0707131","type":"journal-article","created":{"date-parts":[[2007,1,23]],"date-time":"2007-01-23T16:23:53Z","timestamp":1169569433000},"page":"567-576","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Sildenafil reduces <scp>L<\/scp>\u2010NAME\u2010induced severe hypertension and worsening of myocardial ischaemia\u2013reperfusion damage in the rat"],"prefix":"10.1111","volume":"150","author":[{"given":"G","family":"Rossoni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"De Gennaro 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