BIG-ENDOTHELIN-1 CONTRACTS RAT ISOLATED UTERUS VIA A PHOSPHORAMIDON-SENSITIVE ENDOTHELIN-ET(A) RECEPTOR-MEDIATED MECHANISM

The presence of a phosphoramidon-sensitive endothelin-1-converting enz yme was investigated in the rat isolated uterus. Endothelin-1 and its precursor, big-endothelin-1, increased the rate of spontaneous contrac tions and caused tonic contractions. Responses to big-endothelin-1 had a slower start than those to endothelin-1. The tonic contraction indu ced by big-endothelin-1 (10 nM) was nearly abolished by phosphoramidon (100 muM), but the response to an equieffective concentration of endo thelin-1 (3 nM) was not affected. Big-endothelin-1 (EC50 6.7 nM) was o nly 7-fold less potent than endothelin-1 (EC50 0.9 nM), whereas endoth elin-3 was much less potent (EC50 > 100 nM). The endothelin ET(A) rece ptor antagonist, BQ-123 (40, 150 and 600 nM), induced graded rightward shifts of the concentration-response curve for endothelin-1. Schild a nalysis yielded a straight line with a slope not different from unity, and a pA2 value of 7.76. At 100 nM, BQ-123 specifically blocked respo nses to both endothelin-1 (3 nM) and big-endothelin-1 (10 nM), without modifying those to oxytocin (5 nM), acetylcholine (3 muM) or bradykin in (0.5 nM). Our results suggest the presence of phosphoramidon-sensit ive endothelin-converting enzyme and demonstrate the occurrence of fun ctional endothelin ET(A) receptors in the rat uterus.