Differential effects of BQ‐123 against endothelin‐1 and endothelin‐3 on the rat vas deferens: evidence for an atypical endothelin receptor

1 The objectives of the present experiments were to assess the role of ETA receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of plateletactivating factor (PAF) and thromboxane A2 (TxA2) in these actions of ET-1 in rats. 2 Intravenous bolus injection of ET-1 (0.1-2 nmol kg-') into anaesthetized rats induced ST segment elevation of the electrocardiogram in a dose-dependent manner without causing arrhythmias. ST segment elevation developed within 20-90 s and persisted for at least 10-20 min following administration of ET-1. 3 Pretreatment of the animals with the selective endothelin ETA receptor antagonist, FR 139317 (2.5 mg kg-', i.v.) inhibited by 86% the ST segment elevation elicited by ET-l (1 nmol kg-1). Pretreatment with intravenous administration of BM 13505 (1 mg kg-'), a TxA2 receptor antagonist, OKY-046 (10 mg kg-'), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg-') or BN 52021 (10 mg kg-') markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg-' bolus plus 2 mg kg-' h-') did not significantly affect ET-1-induced ST segment elevation. 4 Bolus injection of ET-1 (1 nmol kg-', i.v.) to conscious rats resulted in a prolonged pressor effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia. ET-l enhanced albumin leakage by 87 and 120% in the left ventricle and right atrium, respectively, as measured by the extravasation of Evans blue dye. 5 The selective ETA receptor antagonist, FR 139317 (2.5 mg kg-') significantly blunted the pressor action of ET-1 and the accompanying bradycardia without affecting the depressor response. Furthermore, FR 139317 almost completely abolished the permeability effect of ET-l in both vascular beds studied. 6 Pretreatment of the animals with BM 13505 (1 mg kg-'), OKY-046 (10mg kg-'), WEB 2086 (1 mg kg-') or BN 52021 (10 mg kg-') significantly reduced ET-1 (1 nmol kg-')-induced albumin extravasation both in the left ventricle and right atrium. The PAF receptor antagonists, WEB 2086 and BN 52021 were equally potent inhibitors in the left ventricle, whereas BN 52021 appeared to be a more potent inhibitor than WEB 2086 in the right atrium. Pretreatment with indomethacin (3 mg kg-' plus 2 mg kg-' h-') did not modify the permeability response to ET-1. None of these compounds affected significantly ET-l-induced changes in mean arterial blood pressure and heart rate. 7 These results indicate that intravenous administration of ET-1 provokes ST segment elevation and myocardial oedema and suggest that these events are mediated, in part, through release of secondary mediators, such as PAF and TxA2 via the activation of ETA receptors.

Section: Discussionsupporting

confidence: 92%

Endothelin‐1‐induced myocardial ischaemia and oedema in the rat: involvement of the ET_A receptor, platelet‐activating factor and thromboxane A₂

Filep

Fournier

Földes-Filep

1994

“…The possible existence of a novel contractile endothelin receptor subtype in rat renal artery is supported by reports that a similar BQ123-resistant receptor subtype may occur in other vascular and non-vascular tissues including rat vas deferens (Eglezos et al, 1993), guinea-pig iliac artery (Schoeffter et al, 1993) and rabbit renal artery . Moreover, recent evidence suggests that a novel BQ123-resistant receptor may occur in human vascular smooth muscle preparations including saphenous vein (Bax et al, 1993a), coronary artery (Bax et al, 1993b;Godfraind et al, 1993) and umbilical artery (Bodelsson & Stjernquist, 1993).…”

Section: Discussionmentioning

confidence: 76%

“…Whether the same subtype of ETB receptor mediates both constrictor and dilator responses remains to be clarified. Moreover, although only two subtypes of mammalian endothelin receptor have as yet been cloned, many groups have observed atypical agonist and antagonist potency profiles in radioligand binding and isolated tissue studies, raising the possibility that further subtypes of endothelin receptors occur (Sokolovsky et al, 1993;Bodelsson & Stjernquist, 1993;Bax et al, 1993a,b;Eglezos et al, 1993;Warner et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Characterization of endothelin receptors in rat renal artery in vitro

Clark

Pierre

1995

1 The aim of this study was to investigate the function and characteristics of endothelin receptors in rat main branch renal artery in vitro.2 Endothelin(ET)-l (mean ECjO = 9.8 nM) was approximately 12 fold more potent than ET-3 (mean EC50 = 120 nM) as a contractile agonist and produced a greater maximum response. In contrast, neither of the ETB receptor-selective agonists, alanine1l'3"1 "'ET-1 nor sarafotoxin S6c, (0.1 nM-I1tM), induced any contractile effect, or any relaxant effect in endothelium-intact preparations pre-contracted with the thromboxane A2 mimetic, U-46619. Sarafotoxin S6c (30 nM) also failed to induce any further contraction in tissues pre-contracted with an ECm concentration of ET-1.3 The ETA receptor-selective antagonist, BQ123, behaved as a weak and variable antagonist of the contractile effects of ET-1 (mean pA2 estimates in the range 5.8-6.3). In contrast, BQ123 antagonized ET-3 with a potency (mean pA2= 7.6) consistent with its affinity for ETA receptors. Co-incubation of BQ123 (3 IM) with the putative ETB receptor-selective antagonist, IRL1038 (10lM), produced no greater antagonism of ET-1 responses than was induced by BQ123 (3 JsM) alone. 4 In conclusion, ETB receptors do not appear to be present in rat main branch renal artery. The contractile effects of ET-3 in this tissue seem to be mediated by ETA receptors. While ETA receptors partly mediate the contractile effects of ET-1, these data raise the possibility that a population of novel BQ123-insensitive endothelin receptors may also contribute to this response.

“…In preparations containing ET A receptors, for example, BQ-123 is frequently more potent in inhibiting contractions induced by sarafotoxin S6b (StxS6b) and ET-3, than similar responses to ET-1. Such agonist-dependent antagonist potency has been observed in rat aorta (Sumner et al, 1992), goat cerebral artery (Salom et al, 1993), human saphenous vein (Bax et al, 1993), human coronary artery (Godfraind, 1993), human umbilical artery (Bodelsson & Sjernquist, 1993) and human omental vein (Riezebos et al, 1994), as well as in rat vas deferens (Eglezos et al, 1993). These ®ndings have prompted speculation concerning the possible existence of a population of BQ-123-insensitive ET A receptors (see Bax & Saxena, 1994 for review).…”

Section: Introductionmentioning

confidence: 93%

Comparison of the contractile effects and binding kinetics of endothelin‐1 and sarafotoxin S6b in rat isolated renal artery

Devadason

Henry

1997

1 To date, only two mammalian endothelin (ET) receptors, termed ET A and ET B , have been cloned, sequenced and characterized. However, several functional studies of isolated blood vessels suggest that ET-1-induced contractions may be mediated by multiple ET A receptors. In this study, the ET A receptors in renal arteries isolated from Wistar rats were characterized by isometric tension recording and radioligand binding techniques. 2 ET-1, sarafotoxin S6b (StxS6b) and ET-3 produced concentration-dependent contraction with similar response maxima in endothelium-denuded arteries, whereas the ET B receptor-selective agonist StxS6c was inactive. ET-1 and StxS6b were equipotent and 30 times more potent than ET-3. This agonist pro®le, together with the ®ndings that the ET A receptor-selective antagonists, BQ-123 and FR-139317 caused concentration-dependent, rightward shifts of the concentration-e ect curves to each agonist indicated that ET-1-induced contractions in rat renal artery were mediated via ET A receptors. 5 Thus, di erences in BQ-123 potency against ET-1 and StxS6b-induced contractions in rat renal arteries might be due to di erences in the kinetics of agonist binding, rather than due to the existence of atypical ET A receptors.