CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin

Pulmonary intralobar arteries express heme oxygenase ( HO)- 1 and - 2 and release carbon monoxide ( CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development ( 0.77 +/- 0.06 mN/ mm) in pulmonary vascular rings treated with 15 mu mol/ l chromium mesoporphyrin ( CrMP), an inhibitor of HO- dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO- 2 antisense oligodeoxynucleotides ( ODN), which decrease pulmonary HO- 2 vascular expression and CO release. Hypoxia- induced contraction of vessels treated with CrMP is attenuated ( P < 0.05) by endothelium removal, by CO ( 1 - 100 mu mol/ l) in the bathing buffer, and by endothelin- 1 ( ET- 1) receptor blockade with L- 754142 ( 10 mu mol/ l). CrMP increases ET- 1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration- response curve to ET- 1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP ( 40 mu mol/ kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET- 1 receptor antagonist L- 745142 ( 15 mg/ kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia- induced pulmonary vasoconstriction by reducing ET- 1 vascular levels and sensitivity.