NO and H2O2 mechanisms of guanylate cyclase activation in oxygen-dependent responses of rat pulmonary circulation.
Pulmonary hypoxic vasoconstriction appears to have both endothelium-dependent and -independent regulatory pathways. We have previously described a mechanism of guanylate cyclase activation in isolated pulmonary arteries that is smooth muscle contained and oxygen tension dependent. In this study we examine this mechanism, involving H2O2 metabolism by catalase, and its relationship to endothelial-derived nitric oxide in the regulation of pulmonary artery pressure (PAP) by oxygen tension. Using probes selective for these two distinct mechanisms of guanylate cyclase activation, we found in the isolated buffer-perfused rat lung that 100 microM nitro-L-arginine (NLA), an inhibitor of NO formation, increased baseline PAP from 4.8 +/- 0.6 to 6.0 +/- 0.6 mmHg and hypoxic PAP from 6.8 +/- 0.8 to 8.56 +/- 0.6 mmHg. Aminotriazole (AT), an inhibitor of H2O2 metabolism by catalase, also increased PAP from 4.5 +/- 0.9 to 6.1 +/- 2.0 mmHg (P < or = 0.05) and hypoxic PAP from 6.0 +/- 1.7 to 8.7 +/- 2.7 mmHg (P < or = 0.05). Additionally, while NLA did not affect the vasodilation that occurs upon reoxygenation, AT inhibited the immediate response to reoxygenation. In the presence of both NLA and AT, baseline PAP increased from 4.25 +/- 0.8 to 9.9 +/- 0.92 mmHg (P < or = 0.05), but hypoxia did not significantly increase PAP and the reoxygenation response was inhibited. These data suggest that both NO and H2O2-catalase mechanisms contribute to a similar degree to maintain low PAP under normoxic conditions. The removal of either mediator may contribute to hypoxic vasoconstriction.
Monaco
J A
JA
Department of Experimental Pathology, New York Medical College, Valhalla 10595, USA.
Burke-Wolin
T
T
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D010100:Oxygen / Q000494:pharmacology*; D011312:Pressure; D011651:Pulmonary Artery / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002374:Catalase; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D006162:Guanylate Cyclase; D010100:Oxygen