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Combined inhibition of NO, prostaglandins and EDHFs inhibits ATP‐induced vasodilation in the human leg

Adenosine‐5′‐triphosphate (ATP) can bind to P2y‐purinergicreceptors and induce vasodilation in skeletal muscle, but the precise mechanisms by which this occurs remain unclear. To investigate whether ATP induced vasodilation is mediated by the action of nitric oxide (NO), prostaglandins and/or endothelial‐derived hyperpolarizing factors (EDHFs), we measured leg hemodynamics before and during 5 min of intra‐arterial infusion of ATP (0.41±0.04μmol min−1;mean±SEM) in 8 healthy, male subjects (24±2 years, 76±3 kg) with and without co‐infusion of indomethacin (INDO; 621±17 μg min−1), NG‐mono‐methyl‐L‐arginine (L‐NMMA; 12.4±0.3 mg min−1), tetraethylammonium chloride (TEA; 12.4±0.3 mg min−1) or INDO + L‐NMMA + TEA. Basal leg blood flow (LBF) was 0.46±0.06 l min−1, but was lower with either L‐NMMA (0.32±0.03) or all three inhibitors (0.28±0.06)(P<0.05), whereas infusion of either TEA or INDO had no effect on basal flow. ATP infusion increased LBF to 2.4±0.2 l min−1, but with co‐infusion of either INDO or L‐NMMA alone, or all three inhibitors combined, it was 13±8, 22±8 and 39±5 % lower, respectively, than with ATP infusion alone. Infusion of TEA did not alter the ATP induced hyperemia. The lower LBF with ATP combined with INDO, L‐NMMA and triple blockade was associated with a 8–12% higher blood pressure and a 15–45 % lower vascular conductance, while heart rate and leg VO2 remained similar. These results indicate that both NO and prostaglandins play an important role in ATP mediated vasodilatation, whereas EDHFs appear to be less important.