Pharmacological characterization of the ETA 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 onset, 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. ETH agonists such as IRL-1620 and AGETB-89 were inactive as vasoconstrictors within the range of concentrations examined. Minor chemical modifications of ET-1 amino acids residues in position 7 or 21 decreased significantly the peptide potency; ET-1 analogues with one or none of the disulfide bonds resulted inactive. The vasomotor effect of ETs was blocked in a competitive, reversible, and selective manner by FR 139317 and BQ-123, the latter being about threefold less potent than the former antagonist. The potency of FR 139317 was 20-fold higher to antagonize ET-3 than ET-1, and threefold 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 endothelial cell layer, the vasomotor potency of ET-1 or the antagonist potency of FR 139317 remained unaltered, suggesting that the vasomotor receptors are localized in the arterial smooth muscles. The ET-1-induced vasomotor responses desensitized, an effect not crossed to noradrenaline (NA); perfusion with 10 microM indomethacin did not alter the vasomotor potency of ET-1, excluding the participation of eicosanoids in the arteriolar effects of ET-1. In isolated rings of the rat mesenteric artery, set to record isometric contractions of the circular muscular layer, the potency of the ETs and their structural analogues was as follows; ET-2 = ET-1 = sarafotoxin S6b > ET-3 > sarafotoxin S6c. The C-terminal hexapeptide of ET-1 and [Ala 1,3,11,15]ET-1 were inactive. The ET-1-induced vasoconstriction was antagonized in a concentration-dependent fashion by FR 139317. These results allow to conclude that the ETA receptors present in the arterial mesenteric circulation are localized 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.
Donoso
M V
MV
Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Faundez
H
H
Rosa
G
G
Fournier
A
A
Edvinsson
L
L
Huidobro-Toro
J P
JP
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D007211:Indoles; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C079574:FR 139317; C072247:cyclo(Trp-Asp-Pro-Val-Leu)