Coronary arteriopathy in monkeys following administration of CI-1020, an endothelin A receptor antagonist

A selective nan-peptide endothelin A (ETA) receptor antagonist, CI-1020, wa s administered to cynomolgus monkeys intravenously (iv) for 2 or 4 wk and o rally 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 we ight for 4 wk. Control animals received the vehicle only. In a separate exp eriment, 1 male was infused with 10 mg/kg/hr for 2 wk, and Monastral blue d ye was administered iv to facilitate localization of lesions to the vascula r walls. One female was administered saline and the dye and served as a con trol. 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 swellin g at the catheter site. Macroscopically, extramural coronary arteries appea red 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 coro nary arteries with arteriopathy was observed in the male treated with CI-10 20 at 10 mg/kg/hr for 2 wk. Extramural coronary arteriopathy occurred at al l doses in the 4-wk iv study, with higher incidence occurring in females th an 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 tre atment were characterized by intimal thickening, fragmentation of the inter nal elastic lamina, necrosis and edema of the media, and mixed inflammatory -cell infiltrates in the intima, media, and adventitia. After 4 wk of iv ad ministration, arteriopathy was characterized by segmental disruption of the elastic lamina and intimal and medial fibrosis with complete replacement o f smooth muscle with fibrous tissue. The adventitia was thickened as a resu lt of fibrosis and mixed or mononuclear inflammatory-cell infiltrates. CI-1 020 concentrations were higher in males (1.57 to 29 mu g/ml) than in female s (0.974 to 24.4 mu g/ml) in the iv study. Transient systemic exposure with high maximum plasma concentration (Cmax) (120-352 mu g/ml) in the oral stu dy was insufficient to provoke arterial changes of the same magnitude as th ose noted with continuous iv administration. The regeneration of the media by fibrous tissue and the disruption of the elastic lamina may weaken the a rterial wall and increase the susceptibility of the artery to the developme nt of aneurysm.