Decreased endothelin binding and [Ca2+]i signaling in microvessels of DOCA-salt hypertensive rats

Academic Article

Abstract

  • Objectives and design: The deoxycorticosterone acetate (DOCA)-salt model of hypertension is characterized by elevated vascular endothelin-1 (ET-1) and by reduced contraction to ET-1 in isolated mesenteric small arteries. The decreased contraction to ET-1 may be a compensatory mechanism caused by elevations in ET-1 and arterial pressure. The present study was designed to determine whether down-regulation of endothelin receptors or altered Ca2+ signaling contribute to the decreased contraction to ET-1. Methods and results: Contraction to ET-1 (10-11 to 10-8 mol/l) was significantly reduced in isolated mesenteric small arteries (87-286 μm intraluminal diameter) from DOCA-salt rats compared with placebo rats. Membrane protein was obtained for measurement of [125I]ET-1 receptor binding and ETA receptor expression. Maximum binding was significantly reduced in vascular membranes from DOCA-salt rats (670 ± 71 fmol/mg protein) compared with placebo rats (1165 ± 75 fmol/mg protein), but binding affinity was unchanged. Conversely, ETA receptor protein was increased in DOCA-salt rat vessels. To assess Ca2+ signaling, freshly dissociated mesenteric small artery smooth muscle cells were loaded with fura-2 for measurement of the average myoplasmic free Ca2+ concentration ([Ca2+]i). The ET-1 (10-9 mol/l) induced increase in [Ca2+]i was significantly less in cells from DOCA-salt rats compared with from placebo rats. This effect was not due to a loss of L-type Ca2+ channels since expression was increased in membrane protein from DOCA-salt rats compared with placebo rats, as measured by Western blot analysis. Conclusions: These findings indicate that decreases in receptor binding and Ca2+ signaling contribute to the impaired contraction to ET-1 in DOCA-salt hypertensive rats. However, these changes are not due to reduced expression of ETA receptors or L-type Ca2+ channels. © 2002 Lippincott Williams & Wilkins.
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    Author List

  • Molero MM; Giulumian AD; Reddy VB; Ludwig LM; Pollock JS; Pollock DM; Rusch NJ; Fuchs LC
  • Start Page

  • 1799
  • End Page

  • 1805
  • Volume

  • 20
  • Issue

  • 9