We evaluated the role of endothelin-B- (ETB) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting lethal (sl) rat which carries a naturally occurring deletion in the ETB-receptor gene. Homozygous (sl/sl) rats exhibit abnormal development of the neural crest-derived epidermal melanocytes and the enteric nervous system (ENS), and do not live beyond 1 month because of intestinal aganglionosis and resulting intestinal obstruction. Therefore, the dopamine-β-hydroxylase (D βH) promoter was used to direct ETB transgene expression in sl/sl rats to support normal ENS development. D βH-ETBsl/sl rats live into adulthood and are healthy, expressing ETB-receptor in adrenals and other adrenergic neurons. When homozygous (sl/sl) and wild-type (WT) (+/+) rats, all of which were transgenic, were treated with DOCA and salt for 4 weeks, the homozygous rats exhibited significantly earlier and higher increases in systolic blood pressure than WT rats. The daily oral administration of ABT-627, a selective ETA-receptor antagonist, almost completely suppressed the DOCA-salt-induced hypertension in both groups. Renal dysfunction and histological damage induced by DOCA-salt treatment were more severe in homozygous than in WT rats. Increased and marked vascular hypertrophy of the aorta was also observed in homozygous rats, compared with WT rats. Renal and vascular injuries induced by DOCA and salt were significantly improved by ABT-627 administration. We propose that ETB-receptor-mediated actions are protective factors in the pathogenesis of DOCA-salt-induced hypertension. ETA-mediated actions are at least partly responsible for the increased susceptibility to DOCA-salt-induced hypertension and related tissue injuries in ETB-receptor-deficient rats.
*Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan, †Diabetes and Vascular Research Division, Abbott Laboratories, Abbott Park, Ilinois, U.S.A. and ‡Howard Hughes Medical Institute, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
Address correspondence and reprint requests to Yasuo Matsumura, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
© 2000 Lippincott Williams & Wilkins, Inc.