Caudill T K, Resta T C, Kanagy N L, Walker B R
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5218, USA.
Am J Physiol. 1998 Oct;275(4):R1025-30. doi: 10.1152/ajpregu.1998.275.4.R1025.
Chronic hypoxic exposure has been previously demonstrated to attenuate systemic vasoconstrictor activity to a variety of agents. This attenuated responsiveness is observed not only in conscious animals but in isolated vascular preparations as well. Because hypoxia has been documented to increase heme oxygenase (HO) levels and the subsequent production of the vasodilator CO in vitro, we hypothesized that the blunted reactivity observed with chronic hypoxia (CH) may be in part due to increased HO activity. In thoracic aortic rings from CH rats, cumulative dose-response curves to phenylephrine (PE) in the presence of the nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine (L-NNA) and the HO inhibitor zinc protoporphyrin 9 (ZnPPIX) elicited increased contractility 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 control rats were unaffected by the HO inhibitor. Furthermore, endothelium-denuded rings from either control or CH rats did not exhibit an increase in reactivity to PE following ZnPPIX incubation. ZnPPIX had no effect 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 soluble guanylyl cyclase. The other products of HO enzyme activity, iron and biliverdin, were without effect on vasoreactivity. Thus we conclude that the attenuated vasoreactivity to PE following CH is likely to involve the induction of endothelial HO and the subsequent enhanced production of CO.
先前的研究表明，慢性低氧暴露可减弱机体对多种血管收缩剂的反应。这种反应性减弱不仅在清醒动物中观察到，在离体血管标本中也存在。由于低氧已被证明可在体外增加血红素加氧酶（HO）水平以及随后血管舒张剂一氧化碳（CO）的生成，我们推测慢性低氧（CH）时观察到的反应性减弱可能部分归因于HO活性增加。在CH大鼠的胸主动脉环中，与仅用一氧化氮（NO）合酶抑制剂Nω-硝基-L-精氨酸（L-NNA）处理的CH环相比，在存在L-NNA和HO抑制剂锌原卟啉9（ZnPPIX）的情况下，对去氧肾上腺素（PE）的累积剂量-反应曲线显示收缩性增加。在用HO诱导剂间亚砷酸钠孵育过夜的环中也观察到类似结果。相反，对照大鼠环中的收缩反应不受HO抑制剂影响。此外，对照或CH大鼠的去内皮环在ZnPPIX孵育后对PE的反应性并未增加。ZnPPIX对NO供体S-亚硝基-N-青霉胺引起的舒张反应无影响，表明其作用具有HO抑制特异性。最后，主动脉环对外源性CO表现出剂量依赖性舒张反应，该反应不依赖于内皮且被可溶性鸟苷酸环化酶抑制剂阻断。HO酶活性的其他产物铁和胆绿素对血管反应性无影响。因此，我们得出结论，CH后对PE的血管反应性减弱可能涉及内皮HO的诱导及随后CO生成增加。
