Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension

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

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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 β-hydroxylase (DβH) promoter was used to direct ET(B) transgene expression in sl/sl rats to support normal enteric nervous system development. DβH-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-, 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.

Original languageEnglish (US)
Pages (from-to)2765-2773
Number of pages9
Issue number22
StatePublished - Nov 28 2000


  • Endothelin
  • Hypertension
  • Receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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