Am J Physiol Heart Circ Physiol. 2007 Aug 24; [Epub ahead of print] ROK contribution to endothelin-mediated contraction in aorta and mesenteric arteries following intermittent hypoxia/hypercapnia in rats.Allahdadi KJ, Walker BR, Kanagy NL. 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 microm) IH-C augments ET-1 constrictor sensitivity but diminishes ET-1- induced increases in intracellular [Ca(2+)] suggesting IH-C exposure increases both ET-1 levels and ET-1 stimulated Ca(2+)-sensitization. Because ROK can mediate Ca-sensitization, we hypothesized 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% versus 41 +/-12 and 48 +/- 9% inhibition, respectively). Therefore ROK appears to contribute more to ET-1 contraction in IH-C than 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 [Ca(2+)]i 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 MLCK (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 aorta. Furthermore, ET-1 constriction is MLCK-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 versus large arteries. Key words: intermittent hypoxia , hypercapnia, sleep apnea, endothelin-1, ROK, vascular.
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