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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/H920    most recent 01264.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Allahdadi, K. J. Articles by Kanagy, N. L. PubMed PubMed Citation Articles by Allahdadi, K. J. Articles by Kanagy, N. L.

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