Carbon Monoxide Is an Inhibitory Regulator of Hypoxia-Induced Contraction of Small Pulmonary Arteries.
Hypoxia elicits pulmonary vasoconstriction, endothelin production and expression of heme oxygenase (HO)-1. In small arteries and arterioles of the systemic circulation, HO catalyzes synthesis of carbon monoxide (CO) which attenuates vascular responsiveness to constrictor stimuli. This study examines the hypothesis that HO-derived CO inhibits constrictor responsiveness to hypoxia in rat pulmonary arterial vessels (PA). Experiments were conducted on rings of large PA (ID=1051±78 μm) and small PA (ID=153±12μm) bathed in Krebs buffer and mounted on a wire-myograph for measurement of isometric tension (IT). Exposure to hypooxygenated buffer (PO2 15 mmHg) elicited minimal increase of IT in small PA (0.026±0.008 mN/mm) but in preparations bathed in buffer containing chromium mesoporphyrin (30 μM, CrMP), an inhibitor of HO-dependent CO synthesis, hypoxia elicited a much more intense increase of IT (0.77±0.06 mN/mm, P<0.05). Hypoxia-induced contraction of large PA also was magnified by pretreatment of the vessels with CrMP (from 0.030±0.007 to 0.077±0.016, P<0.05) but the intensity of the response was less than in similarly treated small PA. In small PA treated with CrMP, hypoxia-induced contractions were attenuated by exogenous CO (10 μM) (from 0.77±0.06 to 0.15±0.05 mN/mm); contraction also were reduced in preparations denuded of endothelium (0.27±0.09 versus 0.77±0.06 mN/mm). Hypoxia-induced contractions of endothelium-intact small PA bathed in buffer containing CrMP were greatly inhibited by pretreatment with L754,142 (10 μM), a blocker of endothelin receptors. These data suggest that endogenous CO is an inhibitory regulator of hypoxia-induced contractions in small PA. This action of CO may reflect inhibition of hypoxia-induced endothelin production or of endothelin-induced vascular contraction.