PHARMACOLOGICAL CHARACTERIZATION OF THE ET(A) RECEPTOR IN THE VASCULAR SMOOTH-MUSCLE COMPARING ITS ANALOGOUS DISTRIBUTION IN THE RAT MESENTERIC-ARTERY AND IN THE ARTERIAL MESENTERIC BED

The potency of ET-1, ET-2, and ET-3 to contract the isolated perfused rat arterial mesenteric bed was 2.73 +/- 0.57, 1.63 +/- 0.32, and 144 +/- 30 nM, respectively. The vasomotor effect of the ETs was slow in o nset, persistent but reversible. Sarafotoxin S6b mimicked the ETs with a potency twofold lower than ET-1; sarafotoxin S6c and the C-terminal hexapeptide of ET-1 was inactive. ET(B) agonists such as IRL-1620 and AGETB-89 were inactive as vasoconstrictors within the range of concen trations examined. Minor chemical modifications of ET-1 amino acids re sidues in position 7 or 21 decreased significantly the peptide potency ; ET-I analogues with one or none of the disulfide bonds resulted inac tive. The vasomotor effect of ETs was blocked in a competitive, revers ible, and selective manner by FR 139317 and BQ-123, the latter being a bout threefold less potent than the former antagonist. The potency of FR 139317 was 20-fold higher to antagonize ET-3 than ET-1, and threefo ld higher to block ET-2 than ET-1. In strict analogy to FR 139317, BQ- 123 was 12-fold more potent to antagonize ET-3 than ET-1, and fourfold more potent to antagonize ET-2 than ET-1. Upon removal of the endothe lial cell layer, the vasomotor potency of ET-1 or the antagonist poten cy of FR 139317 remained unaltered, suggesting that the vasomotor rece ptors are localized in the arterial smooth muscles. The ET-l-induced v asomotor responses desensitized, an effect not crossed to noradrenalin e (NA); perfusion with 10 mu M indomethacin did not alter the vasomoto r potency of ET-1, excluding the participation of eicosanoids in the a rteriolar effects of ET-1. In isolated rings of the rat mesenteric art ery, set to record isometric contractions of the circular muscular lay er, the potency of the ETs and their structural analogues was as follo ws: ET-2 = ET-1 = sarafotoxin S6b > ET-3 > sarafotoxin S6c. The C-term inal hexapeptide of ET-1 and [Ala(1,3,11,15)]ET-1 were inactive. The E T-1-induced vasoconstriction was antagonized in a concentration-depend ent fashion by FR 139317. These results allow to conclude that the ET( A) receptors present in the arterial mesenteric circulation are locali zed in the vascular smooth muscle of the large-sized arteries as well as the smaller arterioles and precapillary vessels of the rat arterial mesenteric bed. Copyright (C) 1996 Elsevier Science Inc.