Hemodynamic effects of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary embolism.
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.
Dias-Junior
Carlos A
CA
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Neto-Neves
Evandro M
EM
Montenegro
Marcelo F
MF
Tanus-Santos
Jose E
JE
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
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