Coronary Arterial Lesions in Dogs Treated With an Endothelin Receptor Antagonist

Louden, Calvert; Nambi, Ponnal; Branch, Carrie A.; Gossett, Kent A.; Pullen, Mark; Eustis, Scot L.; Solleveld, Henk A.

doi:10.1097/00005344-199800001-00109

Cited by 18 publications

(14 citation statements)

References 4 publications

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“…Medial smooth muscle cell necrosis was associated with disorganisation or disruption of their basal laminae and those of adjacent cells that also displayed various lucent and dense cytoplasmic inclusions and separation of plasmalemmae from their basal laminae. The observed colocalisation of focal internal elastic lamina damage and medial injury is indicative of a mechanical basis for injury as has been observed following exposure to other vasoactive drugs and implicated as a primary factor in lesion pathogenesis (20,25). Disruption or breaks in the internal elastic lamina were observed in several of our studies.…”

Section: Physiological Assessmentssupporting

confidence: 82%

“…Animals of the same sex and dose group were housed together in controlled environment rooms (15)(16)(17)(18)(19)(20)(21)(22)(23)(24) • C temperature and 40-70% relative humidity) and given 12 hours light/dark illumination. All animals were offered 400 g/day of irradiated SDS Dog Diet A [E] SQC (Special Diet Services, Witham, Essex, UK) and drinking quality tap water ad libitum.…”

Section: Animal Maintenancementioning

confidence: 99%

“…While endothelin antagonists administered parenterally or orally induce coronary arterial damage within 24 hours of administration (2, No evidence of direct arterial toxicity has been demonstrated, and it is probable that the lesions develop as a result of the pharmacological action of endothelin antagonists. Endothelin is an important modulator of arterial tone acting through ET A and a subtype of ET B receptors on smooth muscle cells of the arterial media to promote vasoconstriction (20). Specific ET A receptor antagonism may counter the ET-1 induced smooth muscle cell contraction associated with agonism of a subtype of the ET B receptor located on medial smooth muscle cells, leading to focal dilatation of the flaccid vessel wall, and result in reduced arterial tone that, in unsupported coronary arteries, may lead to focal or multifocal damage.…”

Section: Physiological Assessmentsmentioning

confidence: 99%

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Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

et al. 2003

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Two endothelin antagonists, ZD1611 (3-{4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl}-2,2-dimethylpropanoic acid) and ZD2574 (2-(4-isobutylphenyl)-N -(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide), selective for the ET A receptor and intended for use in pulmonary hypertension, were tested in Beagle dogs at various doses for periods of up to 4 weeks. These studies included in vivo telemetric hemodynamic assessment, full histopathological and ultrastructural pathological evaluation of coronary arteries. Both drugs produced arteritis in small-and medium-sized coronary arteries after single or multiple doses, some of which were at or below the ED50. The distribution of lesions was predominantly in extramural arteries over the atria and atrioventricular groove of the right side of the heart and consisted of epicardial hemorrhage and arteritis. Systemic arteritis was also present at a lower incidence than the coronary arteritis, was located at different sites and appeared inconsistently. Ultrastructural changes in coronary arteries suggested that damage was the result of mechanical factors. Although these patterns of vascular injury possessed features in common with those induced in dogs by high doses of vasodilating antihypertensive drugs and inotropic agents, they were atypical, as there was no left ventricular myocardial necrosis, papillary muscle damage, or subendocardial hemorrhage suggestive of ischaemia or excessive inotropism. Moreover, physiological monitoring showed no evidence of exaggerated systemic hypotension or reflex tachycardia at doses associated with vascular damage. Consequently, the changes might be the result of a localized pharmacological process such as intense, prolonged vasodilatation in unsupported arteries that are well endowed with endothelin receptors and particularly sensitive to endothelin antagonism.

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Section: Physiological Assessmentssupporting

confidence: 82%

Section: Animal Maintenancementioning

confidence: 99%

Section: Physiological Assessmentsmentioning

confidence: 99%

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Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

et al. 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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“…The absence of changes in coronary blood ow may be related to the short duration of this study. Previous studies (10,11,22) with endothelin antagonists (ET A or ET A/ B ) have shown treatment-related vasodilation of coronary arteries as early as 3 hours posttreatment and minor but sustained decreases in mean arterial blood pressure in with prolonged (5-day) treatment.…”

Section: Endothelin-1 Levelsmentioning

confidence: 99%

Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist

et al. 2001

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A selective nonpeptide endotheli n A (ETA) receptor antagonist, CI-1020, was administered to beagle dogs intravenously (iv) for 4 hours to 4 weeks. One animal/sex received CI-1020 at 1 mg/kg/hr intravenousl y for 4, 8, or 24 hours to investigate onset of arteriopathy. Control animals (1/sex) received the vehicle only. To determine reversibility of arteriopathy, 8 dogs/sex were given CI-1020 at 1 mg/kg/hr for 4 days. Two dogs/sex were sacri ced 1, 3, 8, and 29 days following cessation of infusion. Lesion developmen t with prolonged exposure was investigated in 1 male dog. It was given CI-1020 by iv bolus at 120 mg/kg/day for 4 weeks and Monastral blue dye was administered iv to facilitate localization of vascular lesions. Coronary blood ow was determined in 4 dogs infused with CI-1020 at 0.3, 3, and 30 mg/kg for one hour at each dose. Macroscopically, hemorrhage or blue discoloration of Monastral blue was noted in the extramural coronary arteries along the coronary groove and atrium. Histologically, the earliest coronary changes were noted in animals sacri ced after 24 hours of treatment and characterized by medial hemorrhage and necrosis with a few in ltrating neutrophils. In the reversibility study, incidence and severity of arteriopathy was dependen t on time of sacri ce following cessation of infusion. Acute necrotizing in ammation of arteries was present in all animals (n 4) on day 1 postinfusion, whereas on day 8 postinfusion, lesions characterized by medial small pockets of trapped red cells, cell debris, and adventitial thickening were seen in 1 dog/sex. By day 29 postinfusion, coronary arteries were similar to controls. In the dog given daily IV bolus injections of CI-1020 for 4 weeks, arterial in ammatory lesions varied from acute to chronic, although most lesions were considered chronic active. Monastral blue pigments were noted in the wall of most arteries with chronic or chronic active lesions. Acute lesions were similar to those noted in day 1 postinfusion of the reversibility study. Medial smooth muscle necrosis and/or brosis with mixed in ammatory cell in ltrates characterized chronic or chronic active lesions. Smooth muscle proliferation and migration into the intima were also noted. There were no signi cant changes in coronary blood ow, coronary vascular resistance, or mean arterial blood pressure following CI-1020 infusion for 3 hours. In the 24-hour infusion study, plasma endothelin 1 (ET-1) levels were mildly elevated (1.5-4 fold) during CI-1020 infusion when compared to either pretest or control values. These results indicate that administration of endothelin antagonist (CI-1020) to dogs was associated with development of coronary arteriopathy, which was completely resolved within 29 days following cessation of treatment. With prolonged (4-week) CI-1020 treatment, arterial lesions at varying stages of developmen t (acute, chronic active, chronic) were seen, suggesting that tolerance to treatment (up to 4 weeks) does not occur.

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Coronary Arterial Lesions in Dogs Treated With an Endothelin Receptor Antagonist

Cited by 18 publications

References 4 publications

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

Differentiating Spontaneous from Drug-Induced Vascular Injury in the Dog

Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist

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