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 journalArticle

51 Citations (Scopus)

Abstract

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
JournalCirculation
Volume102
Issue number22
StatePublished - Nov 28 2000

Fingerprint

Endothelin B Receptors
Desoxycorticosterone
Metrorrhagia
Blood Vessels
Acetates
Salts
Pathology
Hypertension
Kidney
Endothelins
Enteric Nervous System
Endothelin-1
Mixed Function Oxygenases
Hypertrophy
Dopamine
Blood Pressure
Adrenergic Neurons
Neural Crest
Intestinal Obstruction
Vascular System Injuries

Keywords

  • Endothelin
  • Hypertension
  • Receptors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Matsumura, Y., Kuro, T., Kobayashi, Y., Konishi, F., Takaoka, M., Wessale, J. L., ... Yanagisawa, M. (2000). Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension. Circulation, 102(22), 2765-2773.

Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension. / Matsumura, Y.; Kuro, T.; Kobayashi, Y.; Konishi, F.; Takaoka, M.; Wessale, J. L.; Opgenorth, T. J.; Gariepy, C. E.; Yanagisawa, Masashi.

In: Circulation, Vol. 102, No. 22, 28.11.2000, p. 2765-2773.

Research output: Contribution to journalArticle

Matsumura, Y, Kuro, T, Kobayashi, Y, Konishi, F, Takaoka, M, Wessale, JL, Opgenorth, TJ, Gariepy, CE & Yanagisawa, M 2000, 'Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension', Circulation, vol. 102, no. 22, pp. 2765-2773.
Matsumura Y, Kuro T, Kobayashi Y, Konishi F, Takaoka M, Wessale JL et al. Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension. Circulation. 2000 Nov 28;102(22):2765-2773.
Matsumura, Y. ; Kuro, T. ; Kobayashi, Y. ; Konishi, F. ; Takaoka, M. ; Wessale, J. L. ; Opgenorth, T. J. ; Gariepy, C. E. ; Yanagisawa, Masashi. / Exaggerated vascular and renal pathology in endothelin-B receptor-deficient rats with deoxycorticosterone acetate-salt hypertension. In: Circulation. 2000 ; Vol. 102, No. 22. pp. 2765-2773.
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AU - Kuro, T.

AU - Kobayashi, Y.

AU - Konishi, F.

AU - Takaoka, M.

AU - Wessale, J. L.

AU - Opgenorth, T. J.

AU - Gariepy, C. E.

AU - Yanagisawa, Masashi

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