Phosphoramidon blocks big‐endothelin‐1 but not endothelin‐1 enhancement of vascular permeability in the rat

1 Changes in vascular permeability following intravenous injections of human big‐endothelin‐1 (big‐ET‐1) and endothelin‐1 (ET‐1) were measured by extravasation of Evans blue dye (EB, 20 mg kg−1) in selected tissues. 2 A low dose of big‐ET‐1 (40 pmol kg−1) failed to alter vascular permeability but a dose of 400 pmol kg−1 increased EB extravasation in the trachea, upper and lower bronchi, and lung parenchyma by 55 to 69% (P < 0.05). Vascular permeability was also enhanced in the liver, spleen, kidney, heart, and diaphragm by 20, 14, 41, 25, and 67%, respectively (P < 0.05). 3 Upon injection of ET‐1 (400 pmol kg−1), EB extravasation increased in the upper and lower bronchi, lung parenchyma, liver, pancreas, kidney, heart, and diaphragm. 4 Administration of ET‐1 and big‐ET‐1 was not associated with significant systemic responses. 5 Pretreatment with phosphoramidon (PA) blocked the response to big‐ET‐1 in all tissues examined but this inhibitor failed to alter the response to ET‐1. 6 We conclude from these results that the dose‐dependent increase in vascular permeability induced by big‐ET‐1 in various tissues follows its conversion to ET‐1 by the endothelin converting enzyme, a PA‐sensitive process.