Endothelin A receptor antagonist LU 135252 inhibits hypercholesterolemia-induced, but not deendothelialization-induced, atherosclerosis in rabbit arteries

RATIONALE AND OBJECTIVES. The purpose of the study was to test the capability of the endothelin A receptor antagonist LU 135252 to reduce neointimal formation in rabbits after balloon denudation with and without the presence of hypercholesterolemia. METHODS. Twenty-eight male New Zealand White rabbits underwent balloon denudation of the infrarenal aorta. The animals were randomly assigned to 1 of the 4 groups. After balloon denudation, group 1 (n = 6) and 2 (n = 7) received a standard diet, and group 3 (n = 8) and 4 (n = 7) were fed a 0.5% cholesterol diet. All interventional procedures were performed while the rabbits were under general anesthesia. One week prior to intervention treatment with LU 135252 was started in group 2 and 4. After 6 weeks the animals were killed for morphometric and histological analysis. RESULTS. Rabbits in all treatment groups developed neointimal hyperplasia. By additional systemic treatment with LU 135252, the mean neointima to media ratio was significantly reduced only in the hypercholesterolemic animals of group 4 (neointimal to media ratio area of group 3 vs group 4: 2.07 +/- 0.62 vs 1.41 +/- 0.45, P < 0.05). ET receptor blockade in group 2 and 4 did not have an effect on plasma levels of cholesterol, very low-density lipoprotein-, high-density lipoprotein-, and low-density lipoprotein-cholesterol. CONCLUSION. LU 135252 was efficient in reducing lipid induced atherosclerotic changes but was ineffective in inhibiting restenosis induced by balloon denudation.