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Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKC

Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico

Submitted 31 October 2007 ; accepted in final form 7 December 2007

We reported previously that simulating sleep apnea by exposing rats to eucapnic intermittent hypoxia (E-IH) causes endothelin-dependent hypertension and increases constrictor sensitivity to endothelin-1 (ET-1). In addition, augmented ET-1-induced constriction in small mesenteric arteries (sMA) is mediated by increased Ca²⁺ sensitization independent of Rho-associated kinase. We hypothesized that exposing rats to E-IH augments ET-1-mediated vasoconstriction by increasing protein kinase C (PKC)-dependent Ca²⁺ sensitization. In sMA, the nonselective PKC inhibitor GF-109203x (3 µM) significantly inhibited ET-1-stimulated constriction in E-IH arteries but did not affect ET-1-stimulated constriction in sham arteries. Phospholipase C inhibitor U-73122 (1 µM) also inhibited constriction by ET-1 in E-IH but not sham sMA. In contrast, the classical PKC (cPKC) inhibitor Gö-6976 (1 µM) had no effect on ET-1-mediated vasoconstriction in either group, but a PKC-selective inhibitor (rottlerin, 3 µM) significantly decreased ET-1-mediated constriction in E-IH but not in sham sMA. ET-1 increased PKC phosphorylation in E-IH but not sham sMA. In contrast, ET-1 constriction in thoracic aorta from both sham and E-IH rats was inhibited by Gö-6976 but not by rottlerin. These observations support our hypothesis that E-IH exposure significantly increases ET-1-mediated constriction of sMA through PKC activation and modestly augments ET-1 contraction in thoracic aorta through activation of one or more cPKC isoforms. Therefore, upregulation of a PKC pathway may contribute to elevated ET-1-dependent vascular resistance in this model of hypertension.

sleep apnea; intermittent hypoxia; hypercapnia; endothelin-1; protein kinase C ; vascular smooth muscle cell; mesenteric arteries

This article has been cited by other articles:

				K. J. Allahdadi, T. W. Cherng, H. Pai, A. Q. Silva, B. R. Walker, L. D. Nelin, and N. L. Kanagy Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H434 - H440. [Abstract] [Full Text] [PDF]