RESPONSES TO ENDOTHELIN-1, HUMAN PROENDOTHELIN (1-38) AND PORCINE PROENDOTHELIN (1-39) IN THE RAT ON INTRAVENOUS ADMINISTRATION AND IN THE BLOOD PERFUSED MESENTERY

Human proendothelin (1-38) and porcine proendothelin (1-39) were respectively 4.3 and 19.2 times less potent than endothelin-1 as systemic pressor agents on i.v. administration but the maximum response to the porcine precursor was significantly greater than that to endothelin-1. The time courses of response were very similar for the 3 peptides. All 3 peptides caused dose-dependent depressor responses which preceded the pressor response and the rank order of potency was similar for both these systemic responses. High doses of endothelin-1 and human proendothelin (1-38) were toxic and death was preceded by disturbance of the ECG and, often, by bradycardia. Mesenteric perfusion pressure in situ was increased dose-dependently by all 3 peptides on close arterial administration without being accompanied by systemic pressor responses. The time courses of the responses were again similar. The human and porcine precursors appeared to be equipotent and approx. 10 times less potent than endothelin-1 itself. The highest doses given by this route commonly caused death which was accompained only by falls in systemic blood pressure even though changes in ECG occurred which were similar to those seen after i.v. administration. Discolouration of the gut occurred which suggested extravasation of erythrocytes had occurred. The results lend some support to the hypothesis that there is more than one type of receptor for the endothelin family of peptides and suggest that both human and porcine proendothelin have a direct action at these receptors. However, it is possible that some of their actions in vivo are mediated by rapid conversion to endothelin-1.