title: ROK contribution to endothelin-mediated contraction in aorta and mesenteric arteries following intermittent hypoxia/hypercapnia in rats.
abstract: We reported previously that intermittent hypoxia with CO(2) to maintain eucapnia (IH-C) elevates plasma endothelin-1 (ET-1) and arterial pressure. In small mesenteric arteries (sMA; inner diameter = 150 microm), IH-C augments ET-1 constrictor sensitivity but diminishes ET-1-induced increases in intracellular Ca(2+) concentration, suggesting IH-C exposure increases both ET-1 levels and ET-1-stimulated Ca(2+) sensitization. Because Rho-associated kinase (ROK) can mediate Ca(2+) sensitization, we hypothesized that augmented vasoconstrictor sensitivity to ET-1 in arteries from IH-C-exposed rats is dependent on ROK activation. In thoracic aortic rings, ET-1 contraction was not different between groups, but ROK inhibition (Y-27632, 3 and 10 microM) attenuated ET-1 contraction more in IH-C than in sham arteries (50 +/- 11 and 78 +/- 7% vs. 41 +/- 12 and 48 +/- 9% inhibition, respectively). Therefore, ROK appears to contribute more to ET-1 contraction in IH-C than in sham aorta. In sMA, ROK inhibitors did not affect ET-1-mediated constriction in sham arteries and only modestly inhibited it in IH-C arteries. In ionomycin-permeabilized sMA with intracellular Ca(2+) concentration held at basal levels, Y-27632 did not affect ET-1-mediated constriction in either IH-C or sham sMA and ET-1 did not stimulate ROK translocation. In contrast, inhibition of myosin light-chain kinase (ML-9, 100 microM) prevented ET-1-mediated constriction in sMA from both groups. Therefore, IH-C exposure increases ET-1 vasoconstrictor sensitivity in sMA but not in aorta. Furthermore, ET-1 constriction is myosin light-chain kinase dependent and mediated by Ca(2+) sensitization that is independent of ROK activation in sMA but not aorta. Thus ET-1-mediated signaling in aorta and sMA is altered by IH-C but is dependent on different second messenger systems in small vs. large arteries.
authors.affiliation: Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors.forename: Kyan J
authors.initials: KJ
authors.lastname: Allahdadi
authors.forename: Benjimen R
authors.initials: BR
authors.lastname: Walker
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000008:administration & dosage*; D004789:Enzyme Activation; D006935:Hypercapnia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012891:Sleep Apnea Syndromes / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D054460:rho-Associated Kinases