Intermittent hypoxia augments pulmonary vascular smooth muscle reactivity to NO: regulation by reactive oxygen species

Abstract

Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension. IH causes oxidative stress that may limit bioavailability of the endothelium-derived vasodilator nitric oxide (NO) and thus contribute to this hypertensive response. We therefore hypothesized that increased vascular superoxide anion (O2−) generation reduces NO-dependent pulmonary vasodilation following IH. To test this hypothesis, we examined effects of the O2− scavenger tiron on vasodilatory responses to the endothelium-dependent vasodilator ionomycin and the NO donor S-nitroso- N-acetylpenicillamine in isolated lungs from hypocapnic-IH (H-IH; 3 min cycles of 5% O2/air flush, 7 h/day, 4 wk), eucapnic-IH (E-IH; cycles of 5% O2, 5% CO2/air flush), and sham-treated (air/air cycled) rats. Next, we assessed effects of endogenous O2− on NO- and cGMP-dependent vasoreactivity and measured O2− levels using the fluorescent indicator dihydroethidium (DHE) in isolated, endothelium-disrupted small pulmonary arteries from each group. Both E-IH and H-IH augmented NO-dependent vasodilation; however, enhanced vascular smooth muscle (VSM) reactivity to NO following H-IH was masked by an effect of endogenous O2−. Furthermore, H-IH and E-IH similarly increased VSM sensitivity to cGMP, but this response was independent of either O2− generation or altered arterial protein kinase G expression. Finally, both H-IH and E-IH increased arterial O2− levels, although this response was more pronounced following H-IH, and H-IH exposure resulted in greater protein tyrosine nitration indicative of increased NO scavenging by O2−. We conclude that IH increases pulmonary VSM sensitivity to NO and cGMP. Furthermore, endogenous O2− limits NO-dependent vasodilation following H-IH through an apparent reduction in bioavailable NO.