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

Abstract

1 There are at least two subtypes of vascular endothelin (ET) receptors. Stimulation of the ETA receptors on vascular smooth muscle cells leads to vasoconstriction, whereas activation of the ETB receptors on endothelial cells elicits vasodilatation. Several reports in the literature have suggested the presence of a vasoconstrictor non-ETA receptor on vascular smooth muscle which has pharmacological similarities to the ETB receptor. The present study was undertaken to determine the location of this ETB-like receptor within the vascular system. 2 Fourteen vascular smooth muscle preparations from six species were used to determine the effect of the ETA receptor antagonist, BQ-123, on concentration-response curves elicited by ET-1 and the ability of the ETB 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 ETA receptors. The other group, with vasoconstrictor ETB-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 ETA receptors, although the potency of BQ-123 was quite variable, suggesting the possibility of ETA 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-', i.v.) also caused a marked secondary depressor response (-80± 6 mmHg) that lasted approximately 10 min. The pressor responses suggest that the vasoconstrictor ETB-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 ETA receptors are primarily located on the high pressure side of the circulation. The vasoconstrictor ETB-like receptors appear to be concentrated on the low pressure side.

Gβγ-mediated Prostacyclin Production and cAMP-dependent Protein Kinase Activation by Endothelin-1 Promotes Vascular Smooth Muscle Cell Hypertrophy through Inhibition of Glycogen Synthase Kinase-3

“…Two types of ET1 receptors, termed ET A and ET B , have been cloned (4,5), and they belong to a family of G protein-coupled receptors, whose signaling is mediated by heterotrimeric G proteins (6,7). ET A receptors are expressed primarily on arterial vessels, whereas ET B receptors predominate on the low pressure side of circulation (8). ET A receptors (the focus of this study) are coupled to G q/11 , G i , and G 12/13 classes of G proteins that mediate the contractile and growth promoting effects of ET1 in VSMC through activation of diverse signaling molecules including phospholipase C (PLC) (9), intracellular Ca 2ϩ (10,11), protein kinase C (12), and the extracellular signal-regulated kinase (ERK) (13).…”

Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo

“…They also reported that the expression of ET B receptors is higher in ganglia from hypertensive DOCA-salt rats than in normotensive control rats. Their findings suggest that ET may increase SNA in DOCA-salt hypertension through an action at ET B receptors located on cell bodies of postganglionic sympathetic neurons.We and others have shown that infusion of the selective ET B receptor agonist sarafotoxin 6c (S6c) into conscious rats results in an increase in blood pressure (25,29). Though ET B receptors are known to cause transient hypotension by the release of the vasodilatory peptides nitric oxide, and prostacyclin (17), they also function as clearance receptors to remove circulating ET-1 (15).…”

“…We and others have shown that infusion of the selective ET B receptor agonist sarafotoxin 6c (S6c) into conscious rats results in an increase in blood pressure (25,29). Though ET B receptors are known to cause transient hypotension by the release of the vasodilatory peptides nitric oxide, and prostacyclin (17), they also function as clearance receptors to remove circulating ET-1 (15).…”

Pharmacology of the EndothelinA Receptor Antagonist: LU 135252

“…Venular vasoconstriction, which was much less pronounced, was antagonized only at the higher dose. Since venous vasoconstriction is mediated predominantly by vasoconstrictive ET, receptors located on venous smooth muscle cells (62,63) LU 135252 had no effect at the lower dose. At the high dose of 30 mgkg i.v., LU 135252 seems to interact at least partially with the vasoconstrictive ET, receptors.…”