Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET_A and ET_B) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat, and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32 ~ 38-weeks old) individuals, the ET-1-induced contraction and the relaxation induced by the selective ET_B-receptor agonist IRL1620 were compared between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats) we found as follows. (1) The ET-1-induced contraction was greater, and was attenuated by BQ123 (ET_A antagonist), but not by BQ788 (ET_B antagonist). In the controls, BQ788 augmented this contraction. (2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. (3) ET-1-induced contraction was enhanced by L-NNA (NO-synthase inhibitor), but suppressed by sodium nitroprusside (NO donor). (4) The enhanced ET-1-induced contraction was reduced by MEK/ERK-pathway inhibitors (PD98059 or U0126). (5) ET-1-stimulated ERK activation was increased, as were the ET_A and MEK1/2 protein expressions. (6) mesenteric ET-1 content was increased. These results suggest that upregulation of ET_A, a defect in ET_B-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined here.