Abstract
Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up&sub4;A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up&sub4;A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up&sub4;A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up&sub4;A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X₇R, or P2Y₆R significantly improved EDR in aortas. Vasoconstrictor response to Up&sub4;A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X₇R but not P2Y₆R. Depletion of major endothelial component nitric oxide enhanced Up&sub4;A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X₇R, and P2Y₆R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.