Hyperresponsiveness to ET-1 after treatment with a mixture of ETA and ETB receptor antagonists in the rabbit in vivo and in vitro.
We tested the reversibility of the response to endothelin-1 (ET-1) in the rabbit renal vasculature after termination of an infusion of either a selective ETA receptor antagonist, BQ-123, a selective ETB receptor antagonist, BQ-788, or a mixture of both antagonists. Previous studies from our laboratory have shown that, as in humans, vasoconstriction of the rabbit renal vasculature induced by ET-1 is mediated solely via the activation of ETA receptors. Therefore, a 15-min infusion of BQ-123 (1 microM) prevented the vasoconstrictor response to ET-1 (10 nM). Sixty minutes after the end of the infusion, the vasoconstrictor response to ET-1 was fully restored to control levels. Conversely, when the selective ETB receptor antagonist was administered, the vasoconstrictor response to ET-1 was markedly potentiated. After the infusion of the antagonist was ended there was no further potentiation of the response to ET-1. Co-infusion of supramaximal concentrations of BQ-123 (1 microM) and BQ-788 (10 nM) still reduced by about 90% the vasoconstrictor response to ET-1. However, after removal of the antagonists, the vasoconstriction to ET-1 was potentiated by more than 75% compared to control (n = 8; p < 0.05). Similarly, a mixture of both antagonists was less effective than BQ-123 alone in reducing the pressor effect of ET-1 in anesthetized rabbits. These results show that blockade of ETB receptors produces marked potentiation in the vasoconstrictor responses to ET-1. Furthermore, a rebound hyperresponsiveness is found after treatment with a mixture of BQ-123 and BQ-788. These results suggest that the systemic and renal vasculatures would respond to ET-1 with enhanced vasoconstriction after treatment with mixed ETA/ETB receptor antagonists owing to the slow reversibility of the antagonism of the ETB receptor-mediated release of nitric oxide.
D'Orléans-Juste
P
P
Department of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
Yano
M
M
Maurice
M C
MC
Gratton
J P
JP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)