Antagonism of P2Y 1 ‐induced vasorelaxation by acyl CoA : a critical role for palmitate and 3′‐phosphate

Background and Purpose Acyl derivatives of CoA have been shown to act as antagonists at human platelet and recombinant P2Y 1 receptors, but little is known about their effects in the cardiovascular system. This study evaluated the effect of these endogenous nucleotide derivatives at P2Y 1 receptors natively expressed in rat and porcine blood vessels. Experimental Approach Isometric tension recordings were used to evaluate the effects of CoA , acetyl CoA , palmitoyl CoA ( PaCoA ) and 3′‐dephospho‐palmitoyl‐ CoA on concentration relaxation–response curves to ADP and uridine triphosphate ( UTP ). A F lex S tation monitored ADP ‐ and UTP ‐evoked calcium responses in HEK293 cells. Key Results Acetyl CoA and PaCoA , but not CoA , inhibited endothelium‐dependent relaxations to ADP with apparent selectivity for P2Y 1 receptors (over P2Y 2/4 receptors) in rat thoracic aorta; PaCoA was more potent than acetyl CoA (331‐fold vs. fivefold shift of ADP response curve evoked by 10  μM PaCoA and acetyl CoA , respectively); the apparent pA 2 value for PaCoA was 6.44. 3′‐dephospho‐palmitoyl‐ CoA (10  μM ) was significantly less potent than PaCoA (20‐fold shift). In porcine mesenteric arteries, PaCoA and the P2Y 1 receptor antagonist MRS2500 blocked ADP ‐mediated endothelium‐dependent relaxations; in contrast, they were ineffective against ADP ‐mediated endothelium‐independent relaxation in porcine coronary arteries (which does not involve P2Y 1 receptors). Calcium responses evoked by ADP activation of endogenous P2Y 1 receptors in HEK293 cells were inhibited in the presence of PaCoA , which failed to alter responses to UTP (acting at endogenous P2Y 2 /4 receptors). Conclusions and Implications Acyl derivatives of CoA can act as endogenous selective antagonists of P2Y 1 receptors in blood vessels, and this inhibitory effect critically depends on the palmitate and 3′‐ribose phosphate substituents on CoA .