title: Hemodynamic effects of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary embolism.
abstract: While endogenous nitric oxide (NO) may be relevant to the beneficial hemodynamic effects produced by sildenafil during acute pulmonary embolism (APE), huge amounts of inducible NO synthase (iNOS)-derived NO may contribute to lung injury. We hypothesized that iNOS inhibition with S-methylisothiourea could attenuate APE-induced increases in oxidative stress and pulmonary hypertension and, therefore, could improve the beneficial hemodynamic and antioxidant effects produced by sildenafil during APE. Hemodynamic evaluations were performed in non-embolized dogs treated with saline (n=4), S-methylisothiourea (0.01 mg/kg followed by 0.5 mg/kg/h, n=4), sildenafil (0.3 mg/kg, n=4), or S-methylisothiourea followed by sildenafil (n=4), and in dogs that received the same drugs and were embolized with silicon microspheres (n=8 for each group). Plasma nitrite/nitrate (NOx) and thiobarbituric acid reactive substances (TBARS) concentrations were determined by Griess and a fluorometric assay, respectively. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 25±1.7 mm Hg and by 941±34 dyn s cm(-5) m(-2), respectively. S-methylisothiourea neither attenuated APE-induced pulmonary hypertension, nor enhanced the beneficial hemodynamic effects produced by sildenafil after APE (>50% reduction in pulmonary vascular resistance). While sildenafil produced no change in plasma NOx concentrations, S-methylisothiourea alone or combined with sildenafil blunted APE-induced increases in NOx concentrations. Both drugs, either alone or combined, produced antioxidant effects. In conclusion, although iNOS-derived NO may play a key role in APE-induced oxidative stress, our results suggest that the iNOS inhibitor S-methylisothiourea neither attenuates APE-induced pulmonary hypertension, nor enhances the beneficial hemodynamic effects produced by sildenafil.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Dias-Junior
authors.forename: Evandro M
authors.initials: EM
authors.lastname: Neto-Neves
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Montenegro
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000208:Acute Disease; D000818:Animals; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress; D010879:Piperazines / Q000494:pharmacology*; D011655:Pulmonary Embolism / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D009566:Nitrates; D009573:Nitrites; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D017392:Thiobarbituric Acid Reactive Substances; D007550:Isothiuronium; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; C027744:S-methylisothiopseudouronium