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Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia

¹Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico; ²Department of Pediatrics, The Ohio State University, Columbus, Ohio; and ³Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Submitted 14 December 2007 ; accepted in final form 22 May 2008

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET_A) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 ± 2 to 137 ± 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET_A receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol·kg^–1·day^–1 sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET_A receptor antagonist BQ-123 (10 µM) but not by the ET type B (ET_B) receptor antagonist BQ-788 (100 µM). ET_A receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET_B receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET_A receptors appears to elevate blood pressure in E-IH-exposed rats.

sleep apnea; BQ-123; BQ-788; mitochondrial ribonucleic acid

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