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.