PD‐156707: A Selective Endothelin‐A Receptor Antagonist

Uprichard, Andrew; Metz, Alan; Hallak, Hussein; Haleen, Stephen J.

doi:10.1111/j.1527-3466.1998.tb00347.x

Cited by 11 publications

(11 citation statements)

References 47 publications

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“…Bosentan is a mixed blocker of ET-A and ET-B receptor, and the ET-A blocking effect is dominant over the ET-B blocking effect (12)(13)(14)(15). CI-1020 is a selective blocker of ET-A receptor (12), and its potent blocking effect on fetal ductal constriction in this study shows the ET and ET-A receptor as major mechanisms of pharmacologically induced fetal ductal constriction.…”

mentioning

confidence: 93%

“…We used CI-1020 (Pfizer, Ann Arbor, MI, U.S.A.) to block ET-A receptor. CI-1020 is a selective ET-A receptor blocker, and effective in blocking ET-A after oral administration (13)(14)(15).…”

Section: Animalsmentioning

confidence: 99%

“…Among four ET, including ET-1, ET-2, ET-3, and ET-4, ET-1 is produced in the vascular endothelium, and induces transient vasodilatation through the ET-B receptor and prolonged vasoconstriction by binding to the ET-A receptor of vascular smooth muscle cells (9,10). Recently, potent mixed and selective ET-A and ET-B blockers have been developed (9,10), including bosentan (mixed blocker) (11,12) and CI 1020 (ET-A blocker) (13)(14)(15). The present study was done to prove the role of endogenous ET in fetal ductal constriction in an in vivo study.…”

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Inhibition of In Vivo Constriction of Fetal Ductus Arteriosus by Endothelin Receptor Blockade in Rats

2003

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The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied the preventive effect of a dual ET receptor antagonist (bosentan) and a selective ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near-term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal ductus was constricted by four medications: orogastric administration of indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1, 10, or 100 mg/kg) was injected intraperitoneally either simultaneously with indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally simultaneously with indomethacin. After maternal atlas dislocation, cesarean section, fetal whole-body freezing, and cutting on the freezing microtome, measurements were made of the inner diameters of the ductus, main pulmonary artery, and ascending aorta. Bosentan blocked fetal ductal constriction by indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal constriction was nearly completely blocked by simultaneously administered 100 mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan) and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus arteriosus induced by ductus-constricting agents in rats, indicating that ET and ET-A receptors are essential in fetal ductal constriction. The DA is widely patent in the fetus, and constricts soon after birth (1). Mechanisms of fetal patency and neonatal constriction of the DA are controversial (2-4). Low PO 2 and prostaglandins dilate the fetal DA (2-4). Momma and Toyono (5) showed that NO is a major dilator of the ductus in the preterm fetus. Nakanishi et al. (6) showed increased intracellular calcium of the ductal smooth muscle when constricted by increased oxygen. Coceani and Kelsey (7) suggested a specific role of ET as a mediator of fetal ductal constriction. Their recent study has shown that deletion of the ET-A receptor suppresses oxygen-induced constriction but not postnatal closure of the DA (8). Among four ET, including ET-1, ET-2, ET-3, and ET-4, ET-1 is produced in the vascular endothelium, and induces transient vasodilatation through the ET-B receptor and prolonged vasoconstriction by binding to the ET-A receptor of vascular smooth muscle cells (9, 10). Recently, potent mixed and selective ET-A and ET-B blockers have been developed (9, 10), including bosentan (mixed blocker) (11,12) and CI 1020 (ET-A blocker) (13-15). The p...

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confidence: 93%

Section: Animalsmentioning

confidence: 99%

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confidence: 99%

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Inhibition of In Vivo Constriction of Fetal Ductus Arteriosus by Endothelin Receptor Blockade in Rats

2003

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“…Medial degeneration and necrosis, adventitial edema, and variable inflammation, can also be associated with chronic proliferative phase of PDE III induced coronary arterial damage (22). Arterial changes induced by PDE III inhibitors are limited in distribution to coronary arteries in which both right and 26 CLEMO ET AL TOXICOLOGIC PATHOLOGY (33), theobromine (11), adrenergic inotropes (isoproterenol, norepinephrine, and dopamine) (41), and various types of endothelin receptor antagonists (2,31,47,49), have been reported to induce, in coronary arteries of dogs, an acute lesion that is morphologically similar to that described for PDE III inhibitors. Administration of CI-1020, an endothelin A receptor antagonist, resulted in medial smooth muscle necrosis and hemorrhage of extramural coronary arteries in dogs treated with single to multiple intravenous doses ( Figure 1a) (2).…”

Section: Vasoactive Induced Arterial Lesions In the Dogmentioning

confidence: 99%

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

et al. 2003

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When vascular injury is observed in dogs used in preclinical toxicology studies, careful evaluation of the lesions is warranted, especially when differentiating drug-induced vascular changes from spontaneous findings, such as idiopathic canine polyarteritis. The clinical signs as well as the nature and distribution of lesions can often be distinguishing, as is the case with vasoactive drugs, including vasodilators and/or positive inotropes (hydralazine, minoxidil, endothelin receptor antagonists, and phosphodiesterase III inhibitors). For most types of vasodilator-induced vascular injury, the lesion is often restricted to coronary arteries, whereas in idiopathic canine polyarteritis, arterial lesions not only involve coronary arteries, but also medium to small arteries of other organs. In addition, the nature of the changes in vessels yields important clues. Medial and adventitial hemorrhage is generally associated with vasodilator-induced arterial lesion, whereas hemorrhage is generally absent in idiopathic polyarteritis. Although idiopathic canine polyarteritis can generally be differentiated from vasoactive-induced vascular injury in dogs, there are increasing incidences of this type of polyarteritis in dogs receiving any 1 of a number of unrelated classes of compounds, suggestive of an exacerbation of the spontaneous disease. Therefore, in order to differentiate drug-induced injury from idiopathic canine polyarteritis, it is critical that examination of the vascular pathology be conducted with good understanding of clinical, pharmacological, and mechanistic data associated with the drug.

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“…Arteriopathy was observed in dogs at doses between 0.3 and 20 mg/kg/hr (27) timal fixation of the heart and the coronary vessels, the heart was removed along with a 3-5-cm segment of attached aorta. The heart was perfused-fixed ex vivo.…”

Section: Introductionmentioning

confidence: 99%

Coronary Arteriopathy in Monkeys Following Administration of CI-1020, an Endothelin A Receptor Antagonist

Albassam¹,

Metz²,

Gragtmans³

et al. 1999

Toxicol Pathol

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A selective non-peptide endothelin A (ET A ) receptor antagonist, CI-1020, was administered to cynomolgus monkeys intravenously (iv) for 2 or 4 wk and orally for 4 wk. Groups consisting of 3 animals of each sex received CI-1020 at 1, 5, and 10 mg/kg/hr (iv) or orally at 250, 500, and 750 mg/kg body weight for 4 wk. Control animals received the vehicle only. In a separate experiment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue dye was administered iv to facilitate localization of lesions to the vascular walls. One female was administered saline and the dye and served as a control. One female at 1 mg/kg/hr was found dead at week 2, and 1 female at 5 mg/kg/hr was euthanatized during week 4 as a result of severe thigh swelling at the catheter site. Macroscopically, extramural coronary arteries appeared thickened and nodular in the 4-wk iv study in the female found dead at 1 mg/kg/hr, in 1 male and 1 female at 5 mg/kg/hr, and in 2 females at 10 mg/kg/hr. Histologically, Monastral blue pigment trapped in the walls of coronary arteries with arteriopathy was observed in the male treated with CI-1020 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at all doses in the 4-wk iv study, with higher incidence occurring in females than in males (7 of 9 treated females compared with 3 of 9 treated males). In the oral study, 1 female at 500 mg/kg/day and 1 male and 2 females at 750 mg/kg/day had coronary arteriopathy. Histological changes after 2 wk of treatment were characterized by intimal thickening, fragmentation of the internal elastic lamina, necrosis and edema of the media, and mixed inflammatory-cell infiltrates in the intima, media, and adventitia. After 4 wk of iv administration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement of smooth muscle with fibrous tissue. The adventitia was thickened as a result of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1020 concentrations were higher in males (1.57 to 29 μg/ml) than in females (0.974 to 24.4 μg/ml) in the iv study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 μg/ml) in the oral study was insufficient to provoke arterial changes of the same magnitude as those noted with continuous iv administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the arterial wall and increase the susceptibility of the artery to the development of aneurysm.

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PD‐156707: A Selective Endothelin‐A Receptor Antagonist

Cited by 11 publications

References 47 publications

Inhibition of In Vivo Constriction of Fetal Ductus Arteriosus by Endothelin Receptor Blockade in Rats

Inhibition of In Vivo Constriction of Fetal Ductus Arteriosus by Endothelin Receptor Blockade in Rats

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

Coronary Arteriopathy in Monkeys Following Administration of CI-1020, an Endothelin A Receptor Antagonist

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