Elevation of blood pressure by genetic and pharmacological disruption of the ET(B) receptor in mice

Takashi Ohuchi, Tomoyuki Kuwaki, Guang Yi Ling, Damiane Dewit, Ki Hwan Ju, Makoto Onodera, Wei Hua Cao, Masashi Yanagisawa, Mamoru Kumada

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Abstract

Exogenously administered endothelin (ET) elicits both pressor and depressor responses through the ET(A) and/or the ET(B) receptor on vascular smooth muscle cells and ET(B) on endothelial cells. To test whether ET(B) has pressor or depressor effects under basal physiological conditions, we determined arterial blood pressure (BP) in ET(B)-deficient mice obtained by crossing inbred mice heterozygous for targeted disruption of the ET(B) gene with mice homozygous for the piebald (s) mutation of the ET(B) gene (ET(B(s/s)). F1 ET(B)(-/s) and ET(B(+/s)) progeny share an identical genetic background but have ET(B) levels that are ~1/8 and 5/8, respectively, of wild-type mice (ET(B)(+/+)). BP in ET(B)(-/s) mice was significantly higher, by ~20 mmHg, than that in ET(B)(+/s) or ET(B)(+/+) mice. Immunoreactive ET- 1 concentration in plasma as well as respiratory parameters was not different between ET(B)(-/s) and ET(B)(+/s) mice. A selective ET(B) antagonist, BQ- 788, increased BP in ET(B)(+/s) and ET(B)(+/+) but not in ET(B)(-/s) mice. Pretreatment with indomethacin, but not with N(G)-monomethyl-L-arginine, can attenuate the observed pressor response to BQ-788. The selective ETA antagonist BQ-123 did not ameliorate the increased BP in ET(B)(-/s) mice. Moreover, BP in mice heterozygous for targeted disruption of the ET(A) gene was not different from that in wild-type controls. These results suggest that endogenous ET elicits a depressor effect through ET(B) under basal conditions, in part through tonic production of prostaglandins, and not through secondary mechanisms involving respiratory control or clearance of circulating ET.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume276
Issue number4 45-4
Publication statusPublished - Apr 1999

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Keywords

  • Endothelin
  • Endothelin receptors
  • Gene targeting
  • Hypertension
  • Indomethacin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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