EFFECTS OF ENDOTHELIN RECEPTOR ANTAGONISTS ON BRADYKININ-INDUCED INCREASES IN MACROMOLECULAR EFFLUX

The goal of this study was to determine the effects of endothelin rece ptor antagonists on agonist-induced increases in macromolecular extrav asation in the hamster cheek pouch in vivo. We used intravital fluores cent microscopy and fluorescein isothiocyanate dextran (FITC-dextran; mol wt = 70 K) to examine extravasation from postcapillary venules in response to bradykinin and endothelin before and following application of inhibitors of endothelin receptors (ET(AB) and ET(A)). Increases i n extravasation of macromolecules were quantitated by counting the num ber of venular leaky sites. Bradykinin (0.5 and 1.0 mu M) and endothel in-1 (0.01 and 0.1 nM) produced a dose-related increase in the number of venular leaky sites and superfusion of PD 142893 (ET(AB) antagonist ), and PD 147953 and BQ-123 (ET(A) antagonists) significantly decrease d bradykinin- and endothelin-induced responses. Addition of calcium to the superfusate restored bradykinin-induced increases in venular leak y sites in the presence of endothelin receptor antagonism. Thus, the f indings of the present study suggest that endothelin receptor antagoni sts abrogate bradykinin- and endothelin-induced increases in macromole cular efflux from postcapillary venules. The mechanism for the effects of endothelin receptor antagonists appears to be related to inhibitio n of the ET(A) receptor which, in turn, alters the mobilization of cal cium across venular endothelium.