Submitted on December 14, 2007
Revised on May 5, 2008
Accepted on May 22, 2008
Endothelin A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia
Kyan J Allahdadi1, Tom W. Cherng2, Hemanth K Pai3, Ana Quenia Gomes da Silva, Benjimen R. Walker4, Leif D Nelin5, and Nancy L. Kanagy6*
1 University of New Mexico Health Science Center
2 University of New Mexico
3 New Mexico Veterans Administration Health Care System
4 University of New Mexico, School of Medicine
5 The Research Institute at Nationwide Children's Hospital
6 University of New Mexico School of Medicine
* To whom correspondence should be addressed. E-mail: nkanagy{at}salud.unm.edu.
We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, augments vascular reactivity to ET-1 and that a non-specific 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 increased ET-1 activation of vascular ETA receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 hrs/day E-IH exposure (109 ± 2 to 137 ± 4 mmHg, p<0.005), but did not change in Sham exposed rats. The ETA receptor antagonist BQ-123 (10 to 1000 nmol/kg, i.v.) acutely decreased MAP dose-dependently in conscious E-IH but not Sham rats and continuous infusion of BQ-123 (100 nmol/kg./day s.c. 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 to those from Sham rats. Constriction was blocked by ETAR antagonist BQ-123 (10 µM) but not by ETBR antagonist BQ-788 (100 µM). ETA receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ETB receptor mRNA was not different in any tissues examined while ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ETAR appears to elevate blood pressure in E-IH-exposed rats.
