Abstract 15930: Uridine Adenosine Tetraphosphate (Up4A)-Induced Coronary Vasodilation is Blunted in Swine with Aortic Banding: A Role for Prostanoids?
Up4A is a potent endothelium-derived contracting factor that contains purine and pyrimidine moieties and activates purinergic P2X and P2Y receptors. Up4A has recently been found to also have vasodilator effects. Here, we evaluated the vasoactive effect of Up4A in isolated coronary small arteries (diameter≈150 µm) from sham (S) swine and swine with severe aortic banding (AoB) (2-month systolic pressure difference of 60 mmHg), and studied the purinergic receptor subtypes and pathways involved. Plasma concentrations of Up4A were much higher in AoB (5.9±3.0 nmol/L) compared to S (0.07±0.03 nmol/L). Surprisingly, Up4A (10-9-10-5 M) failed to induce coronary contraction, but produced dose-dependent relaxation of vessels from S and AoB preconstricted with U46619. Sensitivity to Up4A was lower in AoB than S (Table). In both S and AoB, P1 (8PT) blockade attenuated the Up4A-induced vasodilation. In contrast, A2A (SCH58261), P2X1 (MRS2159), or P2Y1 (MRS2179) blockade attenuated the vasodilator effect of Up4A in S but not in AoB. Furthermore, the effect of Up4A was reduced by nitric oxide synthase inhibition (LNAME) in both S and AoB. Subsequent cycloxygenase inhibition (indomethacin) further attenuated Up4A-induced coronary vasodilation in S, while it enhanced vasodilation in AoB.
In conclusion, Up4A is a dilator rather than a constrictor in coronary microvessels, which in S occurs via P1 (A2A, as well as other adenosine receptor subtypes) and P2X1 and P2Y1 mediated activation of NOS and COX. In AoB, P1 (but not A2A) but not P2X1 and P2Y1 receptors are involved in activation of NOS. Elevated plasma levels of Up4A in AoB cause production of vasoconstrictor prostanoids thereby limiting the vasodilator response to Up4A. These findings indicate that in AoB involvement of different purinergic receptors results in activation of other intracellular pathways.
- © 2012 by American Heart Association, Inc.