Activation of nitric oxide‐cyclic GMP pathway (NO‐cGMP) with nitrite or sildenafil, but not BAY 41‐2272 (BAY), blunts acute pulmonary embolism (APE)‐induced increases in circulating matrix metalloproteinase‐9 (MMP‐9) and oxidative stress

Abstract

ObjectivesOxidative stress is a major upregulator of MMP‐9 and both are induced by APE, thus, we comparatively assessed the effects of NO‐cGMP activators with and without antioxidant properties on APE‐induced increases in MMP‐9.MethodsHemodynamic and biochemical evaluations were performed in non‐embolized dogs treated with saline (N= 5), and in embolized dogs (intravenous injections of microspheres) that received saline (n=9), or nitrite (6.75 µmol/kg over 15 min followed by 0.28 µmol/kg/min; n=5), or sildenafil (0.25 mg/kg over 30 min; n=5), or BAY (0.03, 0.1, 0.3, and 1 mg/kg/h; n=5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations and MMP‐2 and MMP‐9 levels were determined using a fluorometric and gelatin zymography methods, respectively.ResultsAPE increased pulmonary artery pressure by ~25 mmHg. The infusion of each drug (nitrite, BAY, or sildenafil) reversed this increase by ~40% (all P<0.05) and similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the infusion of BAY produced systemic hypotension (P<0.05). While nitrite and sildenafil blunted the increases in plasma MMP‐9 levels and TBARS (all P<0.05), BAY produced no such effects.ConclusionThese findings are consistent with the idea that NO‐cGMP activators with antioxidant effects prevent the release of MMP‐9 during APE. Supported by FAPESP