A64-06 Intermittent Hypoxia Impairs Vasodilation and Promotes Vasoconstriction to Substance P in Mouse Pulmonary Arteries

Rationale Intermittent hypoxia concomitant with sleep apnea leads to pulmonary hypertension. Neuronal function can be altered by IH, however, the effects of IH on sensory nerve-mediated vasoreactivity are poorly defined. The sensory neurotransmitter substance P can evoke both vasodilation and vasoconstriction in pulmonary arteries, and we hypothesized that IH would enhance vasoconstriction to substance P. Methods We evaluated vasoreactivity to substance P (10-9-10-5 M) in isolated, pressurized (16 cmH2O) pulmonary arteries (100-150 µm diameter) preconstricted with uridine triphosphate (UTP, 5 µM; EC50) from male C57BL/6J mice exposed to cycles of IH (90s 6% O2 / 90s room air) or room aim for 12 hr/day for 8 weeks (sham). Changes in smooth muscle cell Vm were evaluated with sharp electrodes. Results In vessels from sham mice, low doses of substance P elicited vasodilation. However, at 10-6 M, substance P transitioned to a vasoconstrictor effect. In pulmonary arteries from IH mice, vasodilation was nearly abolished,and substance P began to elicit vasoconstriction at 10-7.5 M. Consistently, IH reduced hyperpolarization to substance P at low concentrations and enhanced depolarization at higher concentrations. Endothelial disruption eliminated vasodilation to substance P for both sham and IH vessels, however, vasoconstriction remained enhanced in IH vs. sham arteries. Remarkably, inhibition of eNOS with LNAME (10-4 M) unmasks an endothelial component to substance P-mediated vasoconstriction which was similar in magnitude in both sham and IH vessels (∼15%). Conclusion IH associated with sleep apnea potentiates pulmonary arterial vasoconstriction to substance P by impairing endothelium-dependent vasodilation and enhancing smooth muscle-dependent vasoconstriction.