Abstract 208: Altered Cerebrovascular Reactivity Following One Month of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) has been identified as a significant risk factor for stroke. However, little is known regarding the effects of OSA on the cerebrovascular wall. Using a novel rodent model of OSA we assessed the hypothesis that (1) OSA augments endothelin (ET-1) induced constrictions of cerebral arteries and (2) OSA attenuates dilations of cerebral arteries by agonist-induced nitric oxide (NO) release from the cerebrovascular endothelium. The repetitive airway closures associated with OSA lead to intermittent hypoxia/hypercapnia and reoxygenation, increased negative intrathoracic pressures, and arousals. In order to model the physiological consequences of OSA, we have chronically instrumented rats with inflatable endotracheal obstruction devices. Unanesthetized freely-ranging rats underwent 30 apneas/ hour for 8 hours/ day (sleep phase) for 1 month. During apnea pO 2 decreased from 122±3 to 67±3 mm Hg; pCO 2 increased from 43±1 to 51±1 mm Hg; pH decreased from 7.46±0.00 to 7.38±0.01; and hemoglobin O 2 saturation decreased from 94±1 to 82±1 % (n=5 and p<0.05 for each). Following 1 month of OSA blood pressure, plasma ET-1 and NO levels were similar in sham and OSA rats. Using the pressurized cerebral artery preparation, we observed a 17.5-fold increase in sensitivity to ET-1 (n=5-6, p<0.05) after 1 month of OSA. The increased sensitivity of OSA cerebral arteries to ET-1 was abolished by the ET-B receptor antagonist BQ-788 (n=6, NS). Additionally, constrictions to the ET-B specific agonist IRL-1620 were significantly greater in OSA, versus sham, cerebral arteries (n=6, p<0.05). Dilations to ATP (a P2Y 2 agonist which stimulates NO production in the endothelium) were attenuated in cerebral arteries from OSA rats by 40% (n=5-8, p<0.05). However dilations to the NO-donor MAHMA-NOnoate were similar between groups. In conclusion, 1 month of OSA results in (1) increased sensitivity of cerebral arteries to ET-1, likely through upregulation of ET-B receptors on the vascular smooth muscle and (2) decreased endothelial-derived NO production. These data suggest that OSA results in significant alterations to the cerebrovascular wall in the absence of hypertension.