Obstructive sleep apnea (OSA) is a significant risk factor for stroke. However, little is known regarding how OSA affects the cerebrovascular wall. We hypothesized that (A) OSA will attenuate dilations of cerebral arteries by agonist-induced NO release from cerebrovascular endothelium and (B) OSA will upregulate endothelin-1 (ET-1)-mediated constrictions in cerebral arteries. Airway obstructions were induced by chronically implanting inflatable endotracheal obstruction devices (ODs). The ODs were remotely controlled by a computer to produce 30 apneas/hr (10 sec each) during 8 hrs of the sleep cycle in free-ranging rats. 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<0.003 for each). After 4 weeks of apnea blood pressure in OSA rats were similar to that in sham rats (108±1 and 103±1 mmHg respectively). Cerebral arteries were isolated after 4 weeks from sham and OSA rats, mounted on pipettes, and pressurized. Diameter changes of the cerebral arteries were measured after the addition of various agents. 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, the dilations to the NO donor, MAHMA-NOnoate, were similar between groups. Sensitivity to ET-1, an agonist for ET
A
and ET
B
, was increased ~20 fold in OSA arteries. EC
50
s for ET-1 constrictions in cerebral arteries from sham and OSA rats were 10.7 ± 4.3 nM and 0.5 ± 0.4 nM respectively (n=5-6, p=0.01). Constrictions to IRL-1620, a selective ET
B
agonist, were enhanced 11-fold in OSA compared to sham cerebral arteries (n=3-4, p<0.01). In preliminary studies, the increased sensitivity to ET-1in cerebral arteries from OSA rats was attenuated by the ET
B
antagonist, BQ-788. We conclude that OSA produces pathological changes involving decreased endothelial-derived NO production and enhances constrictor responses to ET-1 as a result of ET
B
upregulation. Since blood pressures were similar in the OSA and sham rats, we conclude that cerebrovascular dysfunction can occur with OSA in the absence of coexisting hypertension.
Environmental Factors as Modulators of the Relationship between Obstructive Sleep Apnea and Lesions in the Circulatory System