ROLE OF ENDOTHELIAL CARBON-MONOXIDE IN ATTENUATED VASOREACTIVITY FOLLOWING CHRONIC HYPOXIA

Chronic hypoxic exposure has been previously demonstrated to attenuate systemic vasoconstrictor activity to a variety of agents. This attenu ated responsiveness is observed not only in conscious animals but in i solated vascular preparations as well. Because hypoxia has been docume nted to increase heme oxygenase (HO) levels and the subsequent product ion of the vasodilator CO in vitro, we hypothesized that the blunted r eactivity observed with chronic hypoxia (CH) may be in part due to inc reased HO activity. In thoracic aortic rings from CH rats, cumulative dose-response curves to phenylephrine (PE) in the presence of the nitr ic oxide (NO) synthase inhibitor Nw-nitro-L-arginine (L-NNA) and the H O inhibitor zinc protoporphyrin 9 (ZnPPIX) elicited increased contract ility compared with CH rings treated with only L-NNA. Similar results were observed in rings incubated overnight with the HO-inducing agent sodium m-arsenite. In contrast, contractile responses in rings from co ntrol rats were unaffected by the HO inhibitor. Furthermore, endotheli um-denuded rings from either control or CH rats did not exhibit an inc rease in reactivity to PE following ZnPPIX incubation. ZnPPIX had no e ffect on relaxant responses to the NO donor S-nitroso-N-penicillamine, suggesting that its actions were specific to HO inhibition. Finally, aortic rings exhibited dose-dependent relaxant responses to exogenous CO that were endothelium independent and blocked by an inhibitor of so luble guanylyl cyclase. The other products of HO enzyme activity, iron and biliverdin, were without effect on vasoreactivity. Thus we conclu de that the attenuated vasoreactivity to PE following CH is likely to involve the induction of endothelial HO and the subsequent enhanced pr oduction of CO.