In Vitro Biological Profile of a Highly Potent Novel Endothelin (ET) Antagonist BQ-123 Selective for the ETA Receptor

Ihara, Masaki; Ishikawa, Kiyofumi; Fukuroda, Takahiro; Saeki, Toshihiko; Funabashi, Kaoru; Fukami, Tatsuki; Suda, Hiroyuki; Yano, Mitsuo

doi:10.1097/00005344-199204002-00005

Cited by 108 publications

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“…4), despite the vascular responses (Table 2), indicating conversion of big ET-1 to the vasoactive ET-1. With 8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 for 20 min in five subjects, it could be shown that big ET-1 reduces the M/I values (see RESULTS), further supporting previous results (22) that the big ET-1/ET-1 system affects IS.…”

Section: Discussionsupporting

confidence: 88%

“…With these procedures, optimal effects on peripheral vascular resistance were seen from 30 min after onset of the blocker infusions, and near-optimal effects seemed to persist for at least another 30 min (13,37). The affinity of BQ-123 is Ͼ100,000 times greater for the ET A than for the ETB receptor (22), and the affinity of BQ-788 is Ͼ1,000 times greater for the ET B than for the ETA receptor (23). For each subject, the big ET-1 infusion was initiated at the same time point in the protocols.…”

Section: Methodsmentioning

confidence: 99%

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Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Ahlborg

Lindstrøm

2002

Journal of Applied Physiology

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Ahlborg, Gunvor, and Jonas Lindströ m. Insulin sensitivity and big ET-1 conversion to ET-1 after ETA-or ETBreceptor blockade in humans. J Appl Physiol 93: 2112-2121, 2002. First published September 6, 2002 10.1152/japplphysiol.00477.2002-Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA-or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 (P Ͻ 0.05) but were unchanged after the ETA antagonist BQ-123 ϩ big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 (P Ͻ 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 (P Ͻ 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 (P Ͻ 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1. skeletal muscle; splanchnic blood flow; renal blood flow; mean arterial blood pressure ENDOTHELIN (ET)-1 WAS CHARACTERIZED as well as the gene encoding for the prepropeptide cloned by Yanagisawa et al. (42). ET-1 belongs to a family of vasoactive peptides and is synthesized by the endothelium from its inactive precursor, big ET-1. Vascular endothelial cells secrete both ET-1 and big ET-1 (35). Both peptides are detected in plasma from healthy individuals and increase during, e.g., myocardial infarction (30). The potent and prolonged vasoconstriction in the splanchnic, renal, and pulmonary vascular beds has previously been demonstrated in healthy young individuals during systemic infusion of both ET-1 (39, 40) or its precursor big ET-1 (3, 4). Both big ET-1 and ET-1 are efficiently eliminated in the splanchnic, renal, and skeletal muscle vascular beds (4, 21, 39, 40), and ET-1 is eliminated in the pulmonary circulation as well (40). At a given arterial ET-1 level, the vascular responses to infused big ET-1 are more pronounced than to ET-1 infusion (3, 4), indicating that locally synthesized ET-1 reaches more vascular smooth muscle ET-1 receptors than ET-1 taken up from the blood.The vascular responses can be explained by the presence of two different ET-receptor subtypes: ET A and ET B (8, 34). ET A and ET B are found on vascular smooth muscle cells where both mediate contraction (12, 15), whereas only ET B receptors are located on the endothelial cells and stimulate the production of the vasodilators prostacyclin (16) and nitric oxide (NO) (16,28). ...

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Ahlborg

Lindstrøm

2002

Journal of Applied Physiology

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“…This agrees with experiments using rat perfused lungs where BQ-123 blocks the release of prostacyclin and/or thromboxane A2 induced by ET-1 (D'Orleans-Juste et al, 1992). It also provides a role for ETA receptors, which account for 15% of ET-1 binding in the guinea-pig lung (Ihara et al, 1992a).…”

Section: Discussionmentioning

confidence: 99%

Characterization of ET_B receptors mediating contractions induced by endothelin‐1 or IRL 1620 in guinea‐pig isolated airways: effects of BQ‐123, FR139317 or PD 145065

Battistini

Warner

Fournier

et al. 1994

British J Pharmacology

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We have characterized the receptors mediating contractions to endothelin‐1 (ET‐1) or IRL 1620, an ETB receptor selective agonist, in isolated strips of tissue prepared from different parts of the guinea‐pig airways. We used as antagonists BQ‐123 and FR139317 (ETA receptor‐selective) and PD 145065 (ETA/ETB receptor non‐selective). ET‐1 and IRL 1620 (10−10 m to 10−6 m) caused similar concentration‐dependent contractions of strips of guinea‐pig trachea and upper bronchus. In the guinea‐pig trachea without epithelium or lung parenchyma, IRL 1620 was less potent than ET‐1. In the trachea, contraction to ET‐1 (< 10−8 m) was preceded by a transient relaxation which was inhibited by BQ‐123 (10−5 m) or FR 139317 (10−5 m) or by the removal of the epithelium. The concentration‐response curve to ET‐1 in the trachea was shifted to the right by PD 145065 (10−5 m to 10−4 m). PD 145065 (10−4 m) also inhibited the response to ET‐1 (3 × 10−7 m) by 55%. Contractions induced by IRL 1620 were not affected by BQ‐123 (10−6 m) or FR139317 (10−6 m) but were significantly attenuated by 10−5 m of either antagonist. PD 145065 at 10−6 m strongly attenuated and at 10−5 m abolished contractions induced by IRL 1620. In the trachea, removal of the epithelium potentiated the effects of both agonists. BQ‐123 (10−5 m) had no effect on contractions of the trachea without epithelium induced by ET‐1, but FR139317 (10−5 m) caused a significant inhibition. PD 145065 (10−5 m to 10−4 m) caused a shift to the right of the ET‐1 concentration‐response curve without affecting the contractile effect at 3 × 10−7 m. All three antagonists inhibited contractions induced by IRL 1620. In the upper bronchus, BQ‐123 (10−5 m) did not affect contractions induced by ET‐1, while FR139317 (10−5 m) attenuated (20–26%) only contractions induced by 1–3 × 10−7 m ET‐1. PD 145065 (10−5 m to 10−4 m) caused a shift to the right of the ET‐1 concentration‐response curve. The contractions induced by IRL 1620 were inhibited by BQ‐123 or FR139317 (10−5 m to 10−4 m). PD 145065 (10−6 m) strongly inhibited contractions induced by IRL 1620 and PD 145065 (10−5 m) totally abolished them. The contractile action of ET‐1 in the lung parenchyma was significantly and similarly attenuated by BQ‐123 (10−5 m) or indomethacin (10−5 m), while FR139317 (10−5 m) was less effective. PD 145065 (10−6 to 10−5 m) inhibited contractions to ET‐1. IRL 1620, which is less potent than ET‐1 in this preparation, was antagonized by PD 145065 (10−5 to 10−6 m) but unaffected by BQ‐123 (10−6 m to 10−5 m) or FR139317 (10−6 m). Thus, ETB receptors mediate contractions to ET‐1 in all four guinea‐pig airway preparations. In addition, contractions to ET‐1 in the trachea and lung parenchyma are mediated in part by ETA receptors. In the latter tissue, these ETA receptors mediate contraction through the release of cyclo‐oxygenase metabolites. Similarly, ETA receptors located on the epithelial cells also mediate the release of prostanoids in the trachea with epithelium but they are responsible for transient relaxations. Intere...

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“…Both radioligand and pharmacological studies provided compelling evidence that the guinea-pig trachea is endowed (Ihara et al, 1992). The role of ETA receptor in this muscle is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of such a response to ETs may be related to the relatively small increment found in cyclicAMP production via the ETA receptor. In guinea-pig airways, ETA receptors constitute about 15% of total receptor density in the trachea whereas ETB receptors, which induce phosphatidyl inositol turnover and muscle contraction (Hay, 1989) represent 85% (Ihara et al, 1992). The well-documented reciprocal interaction (cross-talk) between IP3 and cyclicAMP signals in smooth muscles may additionally explain the magnitude of the cyclicAMP increment and consequently the inability of ET-1 to provoke a prominent relaxation in this smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Endothelins‐induce cyclicAMP formation in the guinea‐pig trachea through an ET_A receptor‐ and cyclooxygenase‐dependent mechanism

El‐Mowafy

Abou-Mohamed

1996

British J Pharmacology

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1 The non-selective endothelin agonist, endothelin-1 (ET-1), and the selective ETB receptor agonist, sarafotoxin-S6c (SRTX-c), contracted guinea-pig isolated trachea in a concentration-dependent manner. The EC50 value for ET-1 (11+2.1 nM) was significantly higher than that of SRTX-c (3.2 + 0.21 nM) and the maximal developed tension due to SRTX-c was 42.8+2.3% higher than that produced by ET-1 (P< 0.05). 2 Pretreatment with the ETA antagonist, BQ-610, appreciably enhanced the developed tension due to ET-1 but not SRTX-c. Likewise, the cyclo-oxygenase inhibitor, indomethacin, markedly potentiated the contractile responses to ET-1, but not to SRTX-c. Combining BQ-610 with indomethacin was not more effective than either of them in augmenting ET-l-evoked tension. The results of the present study indicate a negative regulatory role mediated by the ETA receptor on the ETB-triggered mechanical response. This effect is likely to be mediated by activation of adenylate cyclase through a cyclo-oxygenase-dependent mechanism.

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In Vitro Biological Profile of a Highly Potent Novel Endothelin (ET) Antagonist BQ-123 Selective for the ETA Receptor

Cited by 108 publications

References 0 publications

Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Characterization of ET_B receptors mediating contractions induced by endothelin‐1 or IRL 1620 in guinea‐pig isolated airways: effects of BQ‐123, FR139317 or PD 145065

Endothelins‐induce cyclicAMP formation in the guinea‐pig trachea through an ET_A receptor‐ and cyclooxygenase‐dependent mechanism

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In Vitro Biological Profile of a Highly Potent Novel Endothelin (ET) Antagonist BQ-123 Selective for the ETA Receptor

Cited by 108 publications

References 0 publications

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

Characterization of ETB receptors mediating contractions induced by endothelin‐1 or IRL 1620 in guinea‐pig isolated airways: effects of BQ‐123, FR139317 or PD 145065

Endothelins‐induce cyclicAMP formation in the guinea‐pig trachea through an ETA receptor‐ and cyclooxygenase‐dependent mechanism

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Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Insulin sensitivity and big ET-1 conversion to ET-1 after ET_A- or ET_B-receptor blockade in humans

Characterization of ET_B receptors mediating contractions induced by endothelin‐1 or IRL 1620 in guinea‐pig isolated airways: effects of BQ‐123, FR139317 or PD 145065

Endothelins‐induce cyclicAMP formation in the guinea‐pig trachea through an ET_A receptor‐ and cyclooxygenase‐dependent mechanism