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(Circulation. 2000;102:2765.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Exaggerated Vascular and Renal Pathology in Endothelin-B Receptor–Deficient Rats With Deoxycorticosterone Acetate–Salt Hypertension

Yasuo Matsumura, PhD; Toshihiko Kuro, MS; Yutaka Kobayashi, MS; Fumiko Konishi, MS; Masanori Takaoka, PhD; Jerry L. Wessale, PhD; Terry J. Opgenorth, PhD; Cheryl E. Gariepy, MD; Masashi Yanagisawa, MD, PhD

From the Department of Pharmacology (Y.M., T.K., Y.K., F.K., M.T.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan; the Diabetes and Vascular Research Division (J.L.W., T.J.O.), Abbott Laboratories, Abbott Park, Ill; and the Howard Hughes Medical Institute (C.E.G., M.Y), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas.

Background—Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt–induced hypertension. We evaluated the pathological role of ET_B receptors in DOCA-salt–induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET_B receptor gene.

Methods and Results—Homozygous (sl/sl) rats exhibit abnormal development of neural crest–derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine ß-hydroxylase (DßH) promoter was used to direct ET_B transgene expression in sl/sl rats to support normal enteric nervous system development. DßH-ET_B sl/sl rats live into adulthood and are healthy, expressing ET_B receptors in adrenal glands and other adrenergic neurons. When homozygous (sl/sl) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ET_A receptor antagonist, completely suppressed DOCA-salt–induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt–treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.

Conclusions—ET_B-mediated actions are protective in the pathogenesis of DOCA-salt–induced hypertension. Enhanced ET-1 production and ET_A-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET_B receptor–deficient rats.

Key Words: endothelin • receptors • hypertension

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