Increased cerebrovascular sensitivity to endothelin-1 in a rat model of obstructive sleep apnea: a role for endothelin receptor B.

David J Durgan, Randy F Crossland, Eric E Lloyd, Sharon C Phillips, Robert M Bryan

Index: J. Cereb. Blood Flow Metab. 35(3) , 402-11, (2015)

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Abstract

Obstructive sleep apnea (OSA) is associated with cerebrovascular diseases. However, little is known regarding the effects of OSA on the cerebrovascular wall. We tested the hypothesis that OSA augments endothelin-1 (ET-1) constrictions of cerebral arteries. Repeated apneas (30 or 60 per hour) were produced in rats during the sleep cycle (8 hours) by remotely inflating a balloon implanted in the trachea. Four weeks of apneas produced a 23-fold increase in ET-1 sensitivity in isolated and pressurized posterior cerebral arteries (PCAs) compared with PCAs from sham-operated rats (EC50=10(-9.2) mol/L versus 10(-10.6) mol/L; P<0.001). This increased sensitivity was abolished by the ET-B receptor antagonist, BQ-788. Constrictions to the ET-B receptor agonist, IRL-1620, were greater in PCAs from rats after 2 or 4 weeks of apneas compared with that from sham-operated rats (P=0.013). Increased IRL-1620 constrictions in PCAs from OSA rats were normalized with the transient receptor potential channel (TRPC) blocker, SKF96365, or the Rho kinase (ROCK) inhibitor, Y27632. These data show that OSA increases the sensitivity of PCAs to ET-1 through enhanced ET-B activity, and enhanced activity of TRPCs and ROCK. We conclude that enhanced ET-1 signaling is part of a pathologic mechanism associated with adverse cerebrovascular outcomes of OSA.