Increased susceptibility to deoxycorticosterone acetate-salt-induced hypertension in endothelin-B-receptor-deficient rats

Y. Matsumura, T. Kuro, Y. Kobayashi, F. Konishi, M. Takaoka, J. L. Wessale, T. J. Opgenorth, C. E. Gariepy, M. Yanagisawa

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5 Scopus citations


We evaluated the role of endothelin-B- (ET(B)) 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 ET(B)-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 ET(B) transgene expression in sl/sl rats to support normal ENS development. D βH-ET(B) sl/sl rats live into adulthood and are healthy, expressing ET(B)-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 ET(A)-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 ET(B)-receptor-mediated actions are protective factors in the pathogenesis of DOCA-salt-induced hypertension. ET(A)-mediated actions are at least partly responsible for the increased susceptibility to DOCA-salt-induced hypertension and related tissue injuries in ET(B)-receptor-deficient rats.

Original languageEnglish (US)
Pages (from-to)S86-S89
JournalJournal of Cardiovascular Pharmacology
Issue number5 SUPPL. 1
StatePublished - 2000


  • ET(A)-receptor
  • ET(B)-receptor
  • Endothelin (ET)
  • Hypertension
  • Vascular hypertrophy

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine


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