Although insulin resistance (IR) is a major risk factor for coronary artery disease, little is known about the regulation of coronary vascular tone in IR by endothelin-1 (ET-1). We examined ET-1 and PGF₂ induced vasoconstriction in isolated small coronary arteries (SCA; ~250 µM) of Zucker obese rats (ZO) and control Zucker lean rats (ZL). ET-1 response was assessed in the absence and presence of endothelin type A (ET_A, BQ-123) or B (ET_B, BQ-788) or both receptor inhibitors. ZO arteries displayed reduced contraction to ET-1 compared to ZL arteries. In contrast, PGF₂ elicited similar vasoconstriction in both groups. ET_A inhibition diminished the ET-1 response in both groups. ET_B inhibition alone or in combination with ET_A blockade, however, restored the ET-1 response in ZO arteries to the level of ZL arteries. Similarly, inhibition of endothelial nitric oxide (NO) synthase with N-nitro L-arginine methyl ester (L-NAME) enhanced the contraction to ET-1 and abolished the difference between ZO and ZL arteries. In vascular smooth muscle cells from ZO, ET-1-induced elevation of myoplasmic free calcium ([Ca²⁺]_i) (measured by Fluo-4 AM fluorescence) and maximal contraction were diminished compared to ZL both in the presence and absence of L-NAME. However, given increases in [Ca²⁺]_i elicited similar contractions of the VSM cells in both groups. Analysis of protein and total RNA from SCA of ZO and ZL revealed equal expression of ET-1 and the receptors (ET_A and ET_B). Thus, coronary arteries from ZO rats exhibit reduced ET-1-induced vasoconstriction resulting from increased ET_B mediated generation of NO and diminished elevation of myoplasmic [Ca²⁺]_i.