Cold temperatures have adverse effects on the human cardiovascular system. Endothelin-1 (ET-1) is a potent vasoconstrictor. We hypothesized that cold exposure increases ET-1 production and up-regulates ET_A receptors. The aim of this study was to determine the effect of cold exposure on the regulation of the ET system. Four groups of rats (6-7 rats/group) were used. Three groups were exposed to moderate cold (6.7±2°C) for 1, 3, and 5 weeks, respectively, while the remaining group was kept at room temperature (25°C) and served as control. Cold exposure significantly increased ET-1 levels in the heart, mesenteric arteries, renal cortex, and renal medulla. ET_A receptor protein expressions were increased in the heart and renal cortex by cold exposure. ET_B receptor expression, however, was decreased significantly in the heart and renal medulla of cold-exposed rats. Cold exposure significantly increased the ratio of ET_A/ET_B receptors in the heart. Additional four groups of rats (3 rats/group) were used to localize changes in ET_A and ET_B receptors at 1, 3, and 5 weeks after exposure to cold. Immunohistochemical analysis showed that the ET_A receptor immunoreactivity was increased but the ET_B receptor immunoreactivity was decreased in cardiac myocytes of cold-exposed rats. The increased ET_A receptor immunoreactivity was also found in vascular smooth muscle cells (VSMC) of cold-exposed rats. Cold exposure increased ET_A receptor immunoreactivity in tubule epithelial cells in the renal cortex but decreased ET_B receptor immunoreactivity in tubule epithelial cells in the renal medulla. Therefore, cold exposure increased ET-1 production, up-regulated ET_A receptors, and down-regulated ET_B receptors.