The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Coe, Yashu; Haleen, Stephen J.; Welch, Kathleen M.; Liu, Youan; Coceani, Flavio

doi:10.1124/jpet.302.2.672

Cited by 16 publications

(14 citation statements)

References 42 publications

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“…Bosentan is a nonselective antagonist (11 -13), while ambrisentan and CI-1020 are relatively selective for the ET A subtype (12,13,30). In the present study, the competition curve by bosentan of specific [ (Fig.…”

Section: Discussionmentioning

confidence: 46%

Bladder Endothelin-1 Receptor Binding of Bosentan and Ambrisentan

et al. 2014

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Section: Discussionmentioning

confidence: 46%

Bladder Endothelin-1 Receptor Binding of Bosentan and Ambrisentan

et al. 2014

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“…[12][13][14] In the present study, the competition curve by bosentan, ambrisentan and CI-1020 of specific […”

Section: Specific [mentioning

confidence: 73%

“…These results confirmed mainly previous pharmacological observations demonstrating functional significance of ET-1 receptors. [4][5][6][7][8][11][12][13][14]16) …”

Section: Discussionmentioning

confidence: 99%

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Endothelin-1 Receptors in Rat Tissues: Characterization by Bosentan, Ambrisentan and CI-1020

Yokoyama

Osano

Hayashi

et al. 2014

Biological & Pharmaceutical Bulletin

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The present study aimed to characterize comparatively endothelin-1 (ET-1) receptors in rat tissues by radioligand binding assay using [125 I]ET-1 and to examine receptor binding after oral administration of bosentan. Significant amount of specific [125 I]ET-1 binding was detected in the lung, heart, kidney, bladder and cerebral cortex of rats. ET-1, bosentan, ambrisentan, and CI-1020 inhibited specific [125 I]ET-1 binding in these tissues in a concentration-dependent manner. The Hill coefficients of each agent in the rat lung and cerebral cortex and those of bosentan and ET-1 in the heart, kidney and bladder were close to unity, while the Hill coefficients of ambrisentan and CI-1020 in the heart, kidney and bladder were less than one. The nonlinear least squares regression analysis revealed the presence of high-and low-affinity ET-1 receptor sites in these tissues for ambrisentan and CI-1020. Oral administration of bosentan caused a dose-dependent decrease in specific [125 I]ET-1 binding in the rat lung, kidney and bladder, suggesting significant binding of the tissue ET-1 receptors in vivo. In conclusion, it has been shown that a significant amount of pharmacologically relevant ET-1 receptors may exist in rat tissues and that ET-1 receptor antagonists such as bosentan at pharmacological doses may exert some pharmacological effects by binding these ET-1 receptors.Key words endothelin-1 receptor; rat tissue; bosentan; ambrisentan; CI-1020; receptor binding characteristics Endothelin-1 (ET-1) was isolated from the culture media of porcine aortic endothelial cells as the most potent vasoconstrictive peptide identified to date.1) ET-1 is synthesized by both vascular and non-vascular smooth muscle cells.2) In addition to producing potent contractions in vascular smooth muscle, ET-1 can also produce contractions in non-vascular smooth muscles including the urinary bladder.3-8) The biological effects of endothelins are mediated through the specific receptors, ET A and ET B .9,10) Both receptor subtypes of ET A and ET B mediate the vasoconstrictor and pressor actions of endothelins. ET-1 receptors have been shown to be present in several non-vascular tissues such as the heart, kidney and bladder, [3][4][5][6][7][8][9][10] but the receptor properties such as the subtype distribution in these tissues have not been characterized simultaneously. Also, the receptor binding of ET-1 receptor antagonists has not been comparatively examined in different tissues.Bosentan, the first non-peptide endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension, is a nonselective ET A and ET B subtype antagonist, [11][12][13] while ambrisentan and CI-1020 are relatively selective of the ET A subtype.12-14) Ambrisentan has also been approved for the treatment of pulmonary arterial hypertension, and has lower hepatotoxicity and weaker drug interaction. 12,13)

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“…Two previous studies have demonstrated a preventive effect of ET-A receptor blockade on the subsequent development of pulmonary hypertension in an acute hypoxic rat model (25) and in a model of meconium aspiration (26). The beneficial effects of other ET-A receptor antagonists in the treatment of acute pulmonary hypertension have recently been demonstrated in lamb (16,17), and pig (27) models of acute hypoxic pulmonary hypertension, and in a lamb model of congenital diaphragmatic hernia (19). Furthermore, the intravenous combined ET-A and -B receptor antagonist, tezosentan, has been shown to reduce PVR in a model of oleic acidinduced lung injury (28).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

et al. 2004

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Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension. Abbreviations PPHN, persistent pulmonary hypertension of the newborn PVR, pulmonary vascular resistance ET, endothelin iNO, inhaled nitric oxide PPHN occurs when there is a failure of the normal rapid fall in PVR and increase in pulmonary blood flow with the onset of respiration at birth (1). Meconium aspiration syndrome is the single most common cause of PPHN, and can result in significant morbidity and mortality in term and near-term infants (2).The normal transition from the high-resistance fetal circulation to the low-resistance postnatal pulmonary circulation is associated with activation of the endogenous vasodilator nitric oxide-cyclic guanosine 5'-monophosphate pathway, and reduced release of the potent pulmonary vasoconstrictor, ET (3). The ET-1 isopeptide is a 21-amino acid polypeptide (4) that is produced within the pulmonary endothelium by the cleavage of its precursor, pro-ET (big ET), by ET converting enzyme. ET-1 is released by the vascular endothelium, and produces its effects through its interaction with at least two receptor subtypes-the A and B receptors, located on the vascular smooth muscle and endothelium. The pulmonary vasoconstrictor effects of ET-1 result mainly from activation of the G-proteincoupled smooth muscle A receptor, whereas stimulation of the endothelial ET-B receptor has been shown to result in vasodilatation (5). ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmo...

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The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Cited by 16 publications

References 42 publications

Bladder Endothelin-1 Receptor Binding of Bosentan and Ambrisentan

Bladder Endothelin-1 Receptor Binding of Bosentan and Ambrisentan

Endothelin-1 Receptors in Rat Tissues: Characterization by Bosentan, Ambrisentan and CI-1020

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

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