Abstract INTRODUCTION: Recent studies indicate that endothelin-1 (ET-1) and abnormality in the transfer of calcium ions have a role in the atherosclerosis process. Amlodipine can influence the risk factors associated with atherosclerosis, but the possible protective mechanisms of ET-1 are not known. We evaluated the effects of amlodipine and/or high-cholesterol diet on blood and renal tissue concentration of endothelin, as well as the role of ET-1 in the pathophysiology of atherosclerosis in male New Zealand white rabbits. methods: Thirty-six male New Zealand white rabbits were divided into four groups: The normal control group, normal group receiving amlodipine, high-cholesterol diet group and high-cholesterol diet plus amlodipine group. After 8 weeks, all animals were anesthetized and blood or tissues samples were colleted. results: Amlodipine led to significant increase in plasma high-density lipoprotein cholesterol (HDL-C) and decrease in serum triglyceride (TG) in the control group. The plasma level of ET-1 in the atherosclerotic model group increased significantly compared with the control group (p<0.01). After 8 weeks of treatment with amlodipine, ET-1 levels decreased significantly in the control group (p<0.01) and high-cholesterol diet rabbits (p<0.01). Amlodipine administration significantly reduced the tissue levels of endothelin only in high-cholesterol diet rabbits (p<0.01). Eight weeks of high-cholesterol diet (2%) did not induce any atherosclerotic lesion in this artery, and amlodipine had no significant effect. CONCLUSIONS: The increase of lipids and ET-1 in the renal artery and plasma with a high-cholesterol diet is not linked to the early stages of atherosclerotic plaque formation. Amlodipine can reduce levels of ET-1 and lipids, but the mechanisms remain to be determined. Keywords: Renal artery, atherosclerosis, amlodipine, endothelin-1, experimental study.