Studies on coronary arteriopathy in dogs following administration of CI-1020, an endothelin A receptor antagonist.
A selective nonpeptide endothelin A (ETA) receptor antagonist, CI-1020, was administered to beagle dogs intravenously (i.v.) for 4 hours to 4 weeks. One animal/sex received CI-1020 at 1 mg/kg/hr intravenously 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 sacrificed 1, 3, 8, and 29 days following cessation of infusion. Lesion development with prolonged exposure was investigated in 1 male dog. It was given CI-1020 by i.v. bolus at 120 mg/kg/day for 4 weeks and Monastral blue dye was administered i.v. to facilitate localization of vascular lesions. Coronary blood flow 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 sacrificed after 24 hours of treatment and characterized by medial hemorrhage and necrosis with a few infiltrating neutrophils. In the reversibility study, incidence and severity of arteriopathy was dependent on time of sacrifice following cessation of infusion. Acute necrotizing inflammation 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 i.v. bolus injections of CI-1020 for 4 weeks, arterial inflammatory 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 fibrosis with mixed inflammatory cell infiltrates characterized chronic or chronic active lesions. Smooth muscle proliferation and migration into the intima were also noted. There were no significant changes in coronary blood flow, 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 development (acute, chronic active, chronic) were seen, suggesting that tolerance to treatment (up to 4 weeks) does not occur.
Albassam
M A
MA
Pfizer Global Research and Development, Ann Arbor Michigan, 48105, USA. mudher.albassam@pfizer.com
Metz
A L
AL
Potoczak
R E
RE
Gallagher
K P
KP
Haleen
S
S
Hallak
H
H
McGuire
E J
EJ
D000199:Actins / Q000032:analysis; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000473:pathology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003327:Coronary Disease / Q000139:chemically induced* / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004149:Dioxoles / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005260:Female; D006321:Heart / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007124:Immunoenzyme Techniques; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D044022:Receptor, Endothelin A; D013997:Time Factors; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology
D000199:Actins; D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093321:PD 156707; D044022:Receptor, Endothelin A