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1 Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: njernigan{at}salud.unm.edu.
Vasodilatory responses to exogenous nitric oxide (NO) are diminished following exposure to chronic hypoxia (CH) in isolated, perfused rat lungs. We hypothesized that both endothelium-derived reactive oxygen species (ROS) and endothelin-1 (ET-1) mediate this attenuated NO-dependent pulmonary vasodilation following CH. To test this hypothesis, we examined vasodilatory and vascular smooth muscle (VSM) Ca2+ responses to the NO donor, spermine NONOate, in UTP-constricted, isolated pressurized small pulmonary arteries from control and CH rats. Consistent with our previous findings in perfused lungs, we observed attenuated NO-dependent vasodilation following CH in endothelium-intact vessels. However, in endothelium-denuded vessels, responses to spermine NONOate were augmented in CH rats compared to controls, thus demonstrating an inhibitory influence of the endothelium on NO-dependent reactivity following CH. Whereas both the ROS scavenger, tiron, and the ETA receptor antagonist, BQ-123; augmented NO-dependent reactivity in endothelium-intact vessels from CH rats, neither fully restored vasodilatory responses to those observed following endotheliumdenudation in vessels from CH rats. In contrast, the combination of tiron and BQ-123, or the non-selective ET receptor antagonist, PD 145,065, enhanced NO responsiveness in endothelium-intact vessels from CH rats similar to that observed following endotheliumdenudation. We conclude that both endothelium-derived ROS and ET-1 attenuate NOdependent pulmonary vasodilation following CH. Furthermore, CH augments pulmonary VSM reactivity to NO.
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