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ROK contribution to endothelin-mediated contraction in aorta and mesenteric arteries following intermittent hypoxia/hypercapnia in rats

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

Submitted 19 February 2007 ; accepted in final form 13 August 2007

We reported previously that intermittent hypoxia with CO₂ to maintain eucapnia (IH-C) elevates plasma endothelin-1 (ET-1) and arterial pressure. In small mesenteric arteries (sMA; inner diameter = 150 µm), IH-C augments ET-1 constrictor sensitivity but diminishes ET-1-induced increases in intracellular Ca²⁺ concentration, suggesting IH-C exposure increases both ET-1 levels and ET-1-stimulated Ca²⁺ sensitization. Because Rho-associated kinase (ROK) can mediate Ca²⁺ 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 µM) 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 Ca²⁺ 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 µM) 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 Ca²⁺ 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.

sleep apnea; endothelin-1; vascular smooth muscle cells; Rho-associated kinase

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				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]

				K. J. Allahdadi, L. C. Duling, B. R. Walker, and N. L. Kanagy Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKC{delta} Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H920 - H927. [Abstract] [Full Text] [PDF]