Nitrite or sildenafil, but not BAY 41-2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress.
BACKGROUND
Inhibition of matrix metalloproteinases (MMPs) improves the hemodynamics during acute pulmonary embolism (APE) and oxidative stress upregulates MMPs. We compared the effects of different NO-cGMP pathway activators on APE-induced increases in MMPs.


METHODS
Hemodynamic and biochemical evaluations were performed in non-embolized dogs treated with saline (N=5), and in microspheres embolized dogs receiving saline (n=9), or nitrite (6.75 micromol/kg i.v. over 15 min followed by 0.28 micromol/kg/min; n=5), or sildenafil (0.25 mg/kg; n=5), or BAY 41-2272 (0.03, 0.1, 0.3, and 1 mg/kg/h; n=5). Plasma thiobarbituric acid reactive substances (TBARS) concentrations were determined. Zymograms of plasma samples were performed, and in vitro antioxidant effects or inhibition of MMPs by these drugs were examined.


RESULTS
APE increased mean pulmonary artery pressure by ~25 mmHg. Nitrite, BAY 41-2272, or sildenafil reversed this increase by ~40% (P<0.05). Similar effects were seen on the pulmonary vascular resistance. While both nitrite and sildenafil produced no systemic effects, the highest dose of BAY 41-2272 produced systemic hypotension (P<0.05). While nitrite and sildenafil blunted the increases in plasma pro-MMP-9 levels and TBARS (all P<0.05), BAY 41-2272 produced no such effects. Nitrite and sildenafil produced in vitro antioxidant effects and inhibited MMPs only at high concentrations. BAY 41-2272 produced no such effects.


CONCLUSIONS
Activation of the NO-cGMP pathway with nitrite or sildenafil, but not with BAY 41-2272, attenuates APE-induced oxidative stress and increased MMP-9 levels. These findings are consistent with the idea that NO-cGMP pathway activators with antioxidant effects prevent the release of MMP-9 during APE.
Dias-Junior
Carlos A
CA
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
Cau
Stefany B A
SB
Oliveira
Alisson M
AM
Castro
Michele M
MM
Montenegro
Marcelo F
MF
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D061965:Matrix Metalloproteinase Inhibitors; D009573:Nitrites / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage*; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000201:enzymology*; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D061965:Matrix Metalloproteinase Inhibitors; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D013450:Sulfones; D000068677:Sildenafil Citrate; D020780:Matrix Metalloproteinase 9