The dinucleotide uridine adenosine tetraphosphate (Up₄A), which has both purine and pyrimidine moieties, was reported as a novel endothelium-derived contracting factor. Recently, growing evidence has suggested that Up₄A plays an important role in regulation of the cardiovascular function. We previously demonstrated that Up₄A-induced vasoconstrictions are altered in arteries from DOCA-salt hypertensive rats. We have assessed responses to Up₄A shown by renal arteries from type 2 diabetic Goto-Kakizaki (GK) rats (42–46 weeks old) and identified the molecular mechanisms involved. Concentration-dependent contractions to Up₄A were greater in renal arterial rings from the GK than age-matched control Wistar group. In both groups, the inhibition of nitric oxide synthase (with N ^G-nitro-l-arginine) increased the response to Up₄A, whereas the inhibition of cyclooxygenase (COX) (with indomethacin) decreased the response. Specific inhibitors of COX-1 (valeroyl salicylate) and COX-2 (NS398), a thromboxane (TX) receptor (TP) antagonist (SQ29548), and P2 receptor antagonist (suramin) also decreased the response to Up₄A. Protein expressions of COXs in renal arteries were greater in the GK than Wistar group. The production of TXB₂ (a metabolite of TXA₂) by Up₄A did not differ between these groups. Concentration-dependent contractions to U46619, an agonist of the TP receptor, were greater in renal arteries from the GK than Wistar group. The expression of P2X₁ and P2Y₂ receptors did not differ between these groups. These results suggest that enhancement of the Up₄A-induced contraction in renal arteries from GK rats may be attributable to the increased activation of COXs/TP receptor signaling.