Comparative Studies with the Endothelin Receptor Antagonists BQ-123 and PD 142893 Indicate At Least Three Endothelin Receptors

Warner, Timothy D.; Allcock, Graham H.; Mickley, Emma J.; Corder, Roger; Vane, John R.

doi:10.1097/00005344-199322008-00032

Cited by 52 publications

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“…Recent studies have demonstrated that some ETB-receptor antagonists such as IRL1038 or RES-701-1, as well as the ETA/ETB antagonist PD142893, are quite ineffective in antagonizing ETB-receptor-mediated contractile responses of some vascular smooth muscles, in spite of their potent antagonistic effects on the vasodilation mediated by ETB-receptors on endothelial cells (6, 7, 10, 11, 16 -18). One possible way to explain these findings is to assume the existence of two ETB-receptor subtypes, and it has been proposed that the ETB-receptor subtype sensitive to these antagonists should be termed ETB1 and the other insensitive subtype, ETB2 (17,18). Although the ETB-receptor subtypes mediating vasorelaxation and vasoconstriction are sometimes designated as ETB1 and ETB2, respectively (23), the antagonistic potency may be more adequate as a criterion for pharmacological classification of ETB-receptors than the types of responses, as it is possible that both subtypes are located on the smooth muscle and mediate vasoconstriction (7).…”

Section: Resultsmentioning

confidence: 99%

“…In these cases, some investigators have suggested that two subtypes of ETAreceptors may exist (6,12), but others have referred to their observations as "novel", "atypical" or "non-ETA, non-ETB" endothelin receptors (13 -15). Similarly, heterogeneity of ETB-receptors has been pointed out by the use of some ETA/ETB-receptor antagonists such as PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp) or selective ETB-receptor antagonists such as IRL1038 ([Cys11-Cys15]ET-1(11-21)) or RES-701-1 (cyclic(Glyl-Asp9)(Gly-Asn-Trp-His-GlyThr-Ala-Pro-Asp-Trp-Phe-Asn-Tyr-Tyr-Trp) (6,7,10,(16)(17)(18).…”

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Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Nishiyama

Takahara

Takao

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-To study endothelin receptor subtypes that mediate the smooth muscle contraction of human saphenous vein, effects of some endothelin-receptor agonists and antagonists were examined. Endothelin (ET)-l and sarafotoxin 6b (S6b) elicited potent concentration-dependent contractions with similar pD2 values and similar maximal responses. Selective ETB-receptor agonists, sarafotoxin 6c (S6c) and IRL1620 (Suc-[Glu9, Ala'!'15]-endothelin-1(8-21)), also caused contractions, but their maximal responses were about one third of that of ET-1. ET-3 showed a biphasic concentration-responsecurve. An ETA-receptor an-or the combination of these two antagonists hardly affected the contractile effect of ET-1, while each of them markedly antagonized the effects of higher concentrations of ET-3 and S6b. Contractions induced by lower concentrations of ET-3 and S6b were resistant to these antagonists. The concentration-response curves for S6c and IRL1620 were not affected by BQ-123. The effect of IRL1620 was markedly inhibited by PD142893, while S6c-induced contractions were much more resistant to PD142893. These different sensitivities to antagonists suggested heterogeneity of both ETA-and ETB-receptors [ETA! (sensitive to BQ-123), ETA2 (resistant to BQ-123), ETB! (sensitive to PD142893) and ETB2 (resistant to PD142893)] in the human saphenous vein, although contractions mediated by ETB-subtypes have smaller maximal responses than those mediated by the ETA-subtypes.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Nishiyama

Takahara

Takao

et al. 1995

Japanese Journal of Pharmacology

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“…There are several reports proposing the existence of additional ET receptor subtypes, in particular for the ET B receptor category (Bax & Saxena, 1994;Warner et al, 1993;Hay et al, 1996;Yoneyama et al, 1995). These hypotheses are based on binding and, in particular, contraction experiments exploring the eects of receptor antagonists against responses elicited by various ET agonists.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, both receptor subtypes must be blocked before signi®cant inhibition of ET-1-evoked contraction is obtained, indicating marked functional reserve (Henry, 1993;Goldie et al, 1996a, b;Fukuroda et al, 1996). However, based upon pharmacological data using ET agonists and antagonists in various tissues, including the lung, it has been speculated that there may exist ET receptor subtypes in addition to the ET A and ET B receptor populations (Bax & Saxena, 1994;Warner et al, 1993;Hay et al, 1996;Yoneyama et al, 1995). This hypothesis appears to be based, to a large extent, on the insensitivity of ET ligand-induced contractions to the currently available ET receptor antagonists, and, thus far, has not been supported by molecular biological, structural or operational experiments.…”

Section: Introductionmentioning

confidence: 99%

Differential modulation of endothelin ligand‐induced contraction in isolated tracheae from endothelin B (ET_B) receptor knockout mice

Hay

Douglas

et al. 2001

British J Pharmacology

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1 The role of endothelin B (ET B ) receptors in mediating ET ligand-induced contractions in mouse trachea was examined in ET B receptor knockout animals. 2 Autoradiographic binding studies, using [ 125 I]-ET-1, con®rmed the presence of ET A receptors in tracheal and bronchial airway smooth muscle from wild-type (+/+) and homozygous recessive (7/7) ET B receptor knockout mice. In contrast, ET B receptors were not detected in airway tissues from (7/7) mice. 3 In tracheae from (+/+) mice, the rank order of potencies of the ET ligands was sarafotoxin (Stx) S6c4ET-14ET-3; Stx S6c had a lower ecacy than ET-1 or ET-3. In tissues from (7/7) mice there was no response to Stx S6c (up to 0.1 mM), whereas the maximum responses and potencies of ET-1 and ET-3 were similar to those in (+/+) tracheae. ET-3 concentration-response curve was biphasic in (+/+) tissues (via ET A and ET B receptor activation), and monophasic in (7/ 7) preparations (via stimulation of only ET A receptors). 4 In (+/+) preparations SB 234551 (1 nM), an ET A receptor-selective antagonist, inhibited the secondary phase, but not the ®rst phase, of the ET-3 concentration-response curve, whereas A192621 (100 nM), an ET B receptor-selective antagonist, had the opposite eect. In (7/7) tissues SB 234551 (1 nM), but not A192621 (100 nM), produced a rightward shift in ET-3 concentrationresponse curves. 5 The results con®rm the signi®cant in¯uence of both ET A and ET B receptors in mediating ET-1-induced contractions in mouse trachea. Furthermore, the data do not support the hypothesis of atypical ET B receptors. In this preparation ET-3 is not an ET B receptor-selective ligand, producing contractions via activation of both ET A and ET B receptors.

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“…A potent ET A receptor antagonist, cyclic pentapeptide BQ123, was subsequently derived from this substance (Ihara et al, 1992;Spatola & Crozet, 1996). Further extensive structure-activity relationship analysis of the carboxyl terminal of the endothelin peptide led to peptide antagonists that had affinity for both ET A and ET B receptors, such as PD142893 (Warner et al, 1993). Interestingly, most of the endothelin receptor antagonists found in nature are ET A receptor antagonists.…”

Section: The Role Of Mapk In Vascular Endothelin Receptor Upregulationmentioning

confidence: 99%

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

Xu¹,

Sun²,

Edvinsson³

2010

Pharmacology & Therapeutics

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Cardiovascular disease remains as the leading cause of death in the developed world.However, there is limited knowledge about how cardiovascular risk factors actually cause vascular disease. Traditional cardiovascular risk factors include increased circulating levels of low-density lipoproteins, cigarette smoking and hypertension (both strongly related to arterial wall injury), inflammation and atherosclerosis.

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Comparative Studies with the Endothelin Receptor Antagonists BQ-123 and PD 142893 Indicate At Least Three Endothelin Receptors

Cited by 52 publications

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Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Differential modulation of endothelin ligand‐induced contraction in isolated tracheae from endothelin B (ET_B) receptor knockout mice

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

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Comparative Studies with the Endothelin Receptor Antagonists BQ-123 and PD 142893 Indicate At Least Three Endothelin Receptors

Cited by 52 publications

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Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Differential modulation of endothelin ligand‐induced contraction in isolated tracheae from endothelin B (ETB) receptor knockout mice

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

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Differential modulation of endothelin ligand‐induced contraction in isolated tracheae from endothelin B (ET_B) receptor knockout mice