Radioimmunoassay evidence that the pressor effect of big endothelindash1 is due to local conversion to endothelindash1

Compared with endothelin-1 (ET-1), big endothelin-1 (big ET-1) is only weakly active on isolated vascular smooth muscle preparations. However, on systemic administration high doses of big ET-1 (1 nmol.kg-1) are approximately equipotent to ET-1, indicating the existence of an endothelin converting enzyme in the circulation that rapidly converts big ET-1 to ET-1. In this study arterial blood levels of big ET-1 and ET-1 immunoreactivity were measured after bolus i.v. administration of big ET-1 (1 or 3 nmol.kg-1) or ET-1 (1 nmol.kg-1) in anaesthetised male Wistar rats. In addition, the effect of phosphoramidon (10 mg.kg-1) on the pressor response to big ET-1 and its disappearance rate from the circulation were examined. After big ET-1 injection, circulating ET-1 concentrations did not exceed 2% of the big ET-1 level. Phosphoramidon reduced the pressor response to big ET-1 by 93%, but did not alter its rate of clearance from the circulation. Thus exogenous big ET-1 is converted locally in the vasculature and its disappearance from the circulation is not dependent on conversion to ET-1.