Endothelin and structurally related analogs distinguish between endothelin receptor subtypes

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.

Section: Methodsmentioning

confidence: 83%

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

Moreland¹,

McMullen

Abboa-Offei

et al. 1994

“…A differential distribution of ET receptor subtypes has also been demonstrated in the human foetal heart and porcine pulmonary tissues (Nakamichi et al, 1991 (Hemsen et al, 1990;van Papendorp et al, 1991) (Takayanagi et al, 1991;Namiki et al, 1992 (Ihara et al, 1991;Fukurodoa et al, 1992;Moreland et al, 1992;Panek et al, 1992). Studies on mammalian isolated blood vessels indicate that ETA receptors mediate the ET-induced vasoconstriction of arterial smooth muscle whereas ETB receptors are responsible for the contractile response in veins (Moreland et al, 1992).…”

Section: Discussionmentioning

confidence: 97%

Differential localization of endothelin ET_a and ET_B binding sites in human placenta

Rutherford

Wharton

McCarthy

et al. 1993

1 The localization and differential distribution of endothelin (ET) receptor subtypes (ETA and ETB) was investigated in sections of human placenta by use of quantitative in vitro autoradiography and receptor selective ligands.2 Specific, high density ['251]-ET-1 binding sites were localized to the decidua and foetal membranes as well as to arteries and veins in the chorionic plate and throughout the villous tree. Moderate to low density binding was found in the extravillous and villous trophoblast respectively. 6 ET may have a local autocrine or paracrine role in the placenta, acting via specific receptors to influence foetoplacental blood flow and other aspects of placental function.

“…Thus, in the present series of experiments, using guinea-pig and human pulmonary tissues, ET-1-induced contraction of vascular and airway smooth muscle is mediated predominantly via activation of ETA and non-ETA receptors, respectively. In contrast, binding and contraction studies using various ligands provided evidence that contraction of rabbit pulmonary artery was produced predominantly via stimulation of non-ETA receptors, which were designated as being of the ETB receptor subtype (Ihara et al, 1992b;Panek et al, 1992). Furthermore, it was reported recently that bronchoconstriction elicited by aerosol administration of ET-1 in sheep in vivo was antagonized by a specific ET-1 receptor antagonist, and it was concluded that ETA-like receptors predominate in sheep airways (Abraham et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Endothelin receptor subtypes in human and guinea‐pig pulmonary tissues

Hay

Luttmann

Hubbard

et al. 1993

109

1 In this study the endothelin (ET) receptor subtypes mediating contractions produced by ET-1 in human and guinea-pig pulmonary tissues were investigated. In addition the receptor responsible for ET-1-induced prostanoid release in human bronchus was determined.2 In human bronchus and human pulmonary artery ET-l (0.1 nM-0.3 JIM) was a potent and effective contractile agent (pD2 = 7.58 + 0.15, n = 6, and 8.48 + 0.11, n = 7, respectively). BQ-123 (1-10 JiM), a potent and selective ETA receptor antagonist, potently antagonized ET-1-induced contraction in human pulmonary artery (pKB = 6.8 with 1 JIM BQ-123, n = 7) but had no effect in human bronchus (n = 6). 3 Sarafotoxin S6c (0.1 nM-0. IliM), the ETB-selective agonist, did not contract human pulmonary artery (n = 5), but potently and effectively contracted human bronchus: pD2 = 8.41 ± 0.17, maximum response =74.4 ± 3.1% of 1O JM carbachol; n = 5. BQ-123 (1-1 I1M) did not antagonize sarafotoxin S6c-induced contraction in human bronchus (n = 5). 4 ET-1 potently contracted guinea-pig trachea, bronchus, pulmonary artery and aorta (pD2 = 8.15 + 0.14, 7.72 + 0.12, 8.52 + 0.12, and 8.18 ± 0.12, respectively, n = 6-14). BQ-123 (0.1-101M) antagonized ET-1-induced contractions in guinea-pig pulmonary artery (pKB = 6.7 with 1 JIM BQ-123, n = 6), aorta (pKB = 7.1 with 1 JIM BQ-123, n = 6) and trachea (pKB = 6.2 with 1 AIM BQ-123, n = 6) but was without marked effect in bronchus (n = 4). In contrast, sarafotoxin S6c (0.1 nM-0.l JIM) did not contract guinea-pig aorta (n = 4) or guinea-pig pulmonary artery (n = 6) but potently and effectively contracted guinea-pig bronchus: pD2= 8.55 + 0. 1; maximum contraction = 63.6 ± 3.1% of 1O JIM carbachol, n = 4. Sarafotoxin S6c (0.1 nM-0. 1 JIM) was a much less effective agonist in guinea-pig trachea: maximum contraction = 13.9 ± 2.5% of 10 JM carbachol, n = 4; P < 0.0001, compared to bronchus. Contractions produced by sarafotoxin S6c in guinea-pig bronchus or trachea were unaffected by (IO IM, n=4). 5 Significant differences were observed in the efficacy, relative to carbachol, but not the potency of sarafotoxin S6c in guinea-pig airways, with a much greater maximum contractile response in bronchus (69.6 ± 2.4% of 1O JM carbachol, n = 6) or lower region of the trachea (48.5 ± 5.9% of 1OJIM carbachol, n = 6) than in the middle region of the trachea (14.4 ± 4.0% of 10 JiM carbachol, n = 6) or the upper region of the trachea (19.3 ± 2.7% of 1O JM carbachol, n = 6). There were minimal regional differences in either ET-1-induced contraction or the potency of BQ-123 (3 JIM) for inhibition of responses to ET-1 in guinea-pig airways. 6 Release of various prostanoids in human bronchus induced by ET-1 (0.3 JiM) was essentially abolished with 10 IM These data provide evidence that distinct ET receptors mediate ET-1-induced contraction in human pulmonary artery, guinea-pig pulmonary artery and guinea-pig aorta (ETA subtype) compared with human bronchus and guinea-pig bronchus (non-ETA, perhaps ETB subtype). Contractions to ET-1 in guinea-pig trache...