Summary—The vasopressor responses of three natural endothelins (ET‐1, ET‐2, ET‐3) and their precursors, pro‐ETs, were studied in a pithed rat preparation, which allows the profile and the potency of vasoconstrictor agents to be determined in the absence of central control of the cardiovascular system. ET‐1 was found to be 4‐ and 8‐fold more potent in raising blood pressure than ET‐2 and ET‐3, respectively. The immediate precursors of these isopeptides, h‐pro‐ET‐1 (human), p‐pro‐ET‐1 (porcine), pro‐ET‐2 and proET‐3, produced significantly smaller pressor responses than their respective ETs, when measured either as peaks or as areas under the time‐effect curve. Hence, the bioavailability of h‐pro‐ET‐1, p‐pro‐ET‐1 and pro‐ET‐2, assessed on the basis of these two parameters, was approximately 50 of that of their corresponding ET, whereas the bioavailability of pro‐ET‐3 was only 25 that of ET‐3. Phosphoramidon inhibits metallopeptidases, the enzymes that convert pro‐ETs to ETs. The approximate iv doses of phosphoramidon reducing by 50 the pressor effects of the pro‐ETs were 2.5, 0.625, less than 2.5 (this dose produced 75 inhibition) and 5 mg/kg iv for h‐pro‐ET‐1, p‐pro‐ET‐1, pro‐ET‐2 and pro‐ET‐3, respectively. In conclusion, these results indicate that the rat may have more than one pro‐ET converting enzyme, each specific for one of the natural pro‐ETs studied, although the alternative explanation, that there is
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