NO AND H2O2 MECHANISMS OF GUANYLATE-CYCLASE ACTIVATION IN OXYGEN-DEPENDENT RESPONSES OF RAT PULMONARY CIRCULATION

Pulmonary hypoxic vasoconstriction appears to have both endothelium-de pendent and -independent regulatory pathways. We have previously descr ibed 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 b y catalase, and its relationship to endothelial-derived nitric oxide i n 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 mu M nitro-L-arginine (NLA), an inhibitor of NO formation, i ncreased 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 inh ibitor of H2O2. metabolism by catalase, also increased PAP from 4.5 +/ - 0.9 to 6.1 +/- 2.0 mmHg (P less than or equal to 0.05) and hypoxic P AP from 6.0 +/- 1.7 to 8.7 +/- 2.7 mmHg (P less than or equal to 0.05) . Additionally, while NLA. did not affect the vasodilation that occurs upon reoxygenation, AT inhibited the immediate response to reoxygenat ion. In the presence of both NLA and AT, baseline PAP increased from 4 .25 +/- 0.8 to 9.9 +/- 0.92 mmHg (P less than or equal to 0.05), but h ypoxia did not significantly increase PAP and the reoxygenation respon se was inhibited. These data suggest that both NO and H(2)O(2-)catalas e mechanisms contribute to a similar degree to maintain low PAP under normoxic conditions. The removal of either mediator may contribute to hypoxic vasoconstriction.