Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice.
Exogenously administered endothelin (ET) elicits both pressor and depressor responses through the ETA and/or the ETB receptor on vascular smooth muscle cells and ETB on endothelial cells. To test whether ETB has pressor or depressor effects under basal physiological conditions, we determined arterial blood pressure (BP) in ETB-deficient mice obtained by crossing inbred mice heterozygous for targeted disruption of the ETB gene with mice homozygous for the piebald (s) mutation of the ETB gene (ETBs/s). F1 ETB-/s and ETB+/s progeny share an identical genetic background but have ETB levels that are approximately (1)/(8) and (5)/(8), respectively, of wild-type mice (ETB+/+). BP in ETB-/s mice was significantly higher, by approximately 20 mmHg, than that in ETB+/s or ETB+/+ mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different between ETB-/s and ETB+/s mice. A selective ETB antagonist, BQ-788, increased BP in ETB+/s and ETB+/+ but not in ETB-/s mice. Pretreatment with indomethacin, but not with NG-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 ETB-/s mice. Moreover, BP in mice heterozygous for targeted disruption of the ETA gene was not different from that in wild-type controls. These results suggest that endogenous ET elicits a depressor effect through ETB under basal conditions, in part through tonic production of prostaglandins, and not through secondary mechanisms involving respiratory control or clearance of circulating ET.
Ohuchi
T
T
Department of Physiology, Faculty of Medicine, The University of Tokyo, Tokyo 113, Japan.
Kuwaki
T
T
Ling
G Y
GY
Dewit
D
D
Ju
K H
KH
Onodera
M
M
Cao
W H
WH
Yanagisawa
M
M
Kumada
M
M
D000818:Animals; D001769:Blood / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005740:Gases / Q000097:blood; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012119:Respiration / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005740:Gases; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019323:omega-N-Methylarginine; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D007213:Indomethacin