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Am J Physiol Lung Cell Mol Physiol 282: L703-L712, 2002. First published November 9, 2001; doi:10.1152/ajplung.00272.2001
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Vol. 282, Issue 4, L703-L712, April 2002

Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats

D. Dunbar Ivy1, Masashi Yanagisawa3, Cheryl E. Gariepy3, Sarah A. Gebb2, Kelley L. Colvin1, and Ivan F. McMurtry2

1 Pediatric Heart Lung Center and Sections of Pediatric Cardiology and 2 Cardiovascular Pulmonary Research Laboratory, University of Colorado School of Medicine, and The Children's Hospital, Denver, Colorado 80218; and 3 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ETA) receptor causes vasoconstriction, stimulation of ET type B (ETB) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ETB receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ETB receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ETB receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was fivefold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F1alpha , a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ETB receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.

endothelin receptors; hypoxia; pulmonary circulation; nitric oxide; prostacyclin


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