Enhancement by endothelin‐1 of microvascular permeability via the activation of ETA receptors

Abstract

1 The objective of the present experiments was to assess the involvement of endothelin-A (ET_A) receptors in mediating the effects of endothelin-1 on microvascular permeability in conscious rats. 2 Bolus injection of endothelin-1 (0.1 and 1 nmol kg⁻¹, i.v.) resulted in a dose-dependent prolonged pressor effect preceded by a transient depressor response. These changes were accompanied by a dose-dependent loss of plasma volume. Endothelin-1 (1 nmol kg⁻¹) enhanced the vascular permeability of the upper and lower bronchi, kidney, stomach, duodenum and spleen (up to 270%) as measured by the extravasation of Evans blue dye. 3 Pretreatment of the animals with the selective ET_A receptor antagonist, BQ-123 (1 mg kg⁻¹, i.v.) significantly blunted the pressor response to endothelin-1 without affecting the depressor response. BQ-123 inhibited by 87% the endothelin-1 (1 nmol kg⁻¹)-induced plasma volume loss. BQ-123 markedly attenuated protein extravasation elicited by endothelin-1 in the upper and lower bronchi and kidney, whereas it completely inhibited the permeability effect of endothelin-1 in the stomach and duodenum. BQ-123 by itself had no significant effect on the parameters studied. 4 The endothelin-1 analogue, [Trp(For)²¹]-endothelin-1, in which Trp²¹ is formylated, was as potent a pressor agent as endothelin-1, but had no depressor action. Bolus injection of [Trp(For)²¹]-endothelin-l (0.1 and 1 nmol kg⁻¹, i.v.) evoked similar plasma volume losses to those observed following administration of equimolar doses of endothelin-1. Furthermore, 1 nmol kg⁻¹ [Trp(For)²¹]-endothelin-l evoked increases in protein extravasation similar to endothelin-1, 1 nmol kg⁻¹. 5 The present findings suggest that endothelin-1 enhances microvascular permeability, in part, via the activation of ET_A receptors.