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

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Abstract
The objective of the present experiments was to assess the involvement of endothelin‐A (ETA) receptors in mediating the effects of endothelin‐1 on microvascular permeability in conscious rats. 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. Pretreatment of the animals with the selective ETA 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. 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. The present findings suggest that endothelin‐1 enhances microvascular permeability, in part, via the activation of ETA receptors.