Evidence for a differential location of vasoconstrictor endothelin receptors in the vasculature.

1 There are at least two subtypes of vascular endothelin (ET) receptors. Stimulation of the ET(A) receptors on vascular smooth muscle cells leads to vasoconstriction, whereas activation of the ET(B) receptors on endothelial cells elicits vasodilatation. Several reports in the literature have suggested the presence of a vasoconstrictor non-ET(A) receptor on vascular smooth muscle which has pharmacological similarities to the ET(B) receptor. The present study was undertaken to determine the location of this ET(B)-like receptor within the vascular system. 2 Fourteen vascular smooth muscle preparations from six species were used to determine the effect of the ET(A) receptor antagonist, BQ-123, on concentration-response curves elicited by ET-1 and the ability of the ET(B) receptor agonist, sarafotoxin S6c, to cause contraction. The vessels fell into two categories. One group was sensitive to BQ-123 and insensitive to sarafotoxin S6c and, thus, probably contained ET(A) receptors. The other group, with vasoconstrictor ET(B)-like receptors, was insensitive to BQ-123 and sensitive to sarafotoxin S6c. 3 Vessels from cynomolgus monkeys, when studied in vitro, appeared to contain primarily ET(A) receptors, although the potency of BQ-123 was quite variable, suggesting the possibility of ET(A) receptor subtypes. In contrast, both ET-1 and sarafotoxin S6c, given as intravenous injections in conscious monkeys, produced transient, equipotent, and dose-related increases in blood pressure. The highest dose of sarafotoxin S6c (1 nmol kg(-1), i.v.) also caused a marked secondary depressor response (- 80 +/- 6 mmHg) that lasted approximately 10 min. The presser responses suggest that the vasoconstrictor ET(B)-like receptors are present in cynomolgus monkeys. 4 The data suggest the presence of two distinct vasoconstrictor ET receptor subtypes on smooth muscle cells. The ET(A) receptors are primarily located on the high pressure side of the circulation. The vasoconstrictor ET(B)-like receptors appear to be concentrated on the low pressure side.