Crecelius AR, Kirby BS, Richards JC, Garcia LJ, Voyles WF, Larson DG, Luckasen GJ, Dinenno FA. Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins. Am J Physiol Heart Circ Physiol 301: H1302-H1310, 2011. First published July 22, 2011; doi:10.1152/ajpheart.00469.2011.-ATP is an endothelium-dependent vasodilator, and findings regarding the underlying signaling mechanisms are equivocal. We sought to determine the independent and interactive roles of nitric oxide (NO) and vasodilating prostaglandins (PGs) in ATP-mediated vasodilation in young, healthy humans and determine whether any potential role was dependent on ATP dose or the timing of inhibition. In protocol 1 (n ϭ 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthaseand cyclooxygenase (ketorolac). Forearm blood flow (FBF) was measured via venous occlusion plethysmography and forearm vascular conductance (FVC) was calculated. In this protocol, neither individual nor combined NO/PG inhibition had any effect on the vasodilatory response (P ϭ 0.22-0.99). In protocol 2 (n ϭ 16), we determined whether any possible contribution of both NO and PGs to ATP vasodilation was greater at low vs. high doses of ATP and whether inhibition during steady-state infusion of the respective dose of ATP impacted the dilation. FBF in this protocol was measured via Doppler ultrasound. In protocol 2, infusion of low (n ϭ 8)-and high-dose (n ϭ 8) ATP for 5 min evoked a significant increase in FVC above baseline (low ϭ 198 Ϯ 24%; high ϭ 706 Ϯ 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low-and high-dose ATP (P Ͻ 0.05), and in a subsequent trial with continuous NO/PG blockade, the vasodilator response from baseline to 5 min of steady-state infusion was similarly reduced for both low (⌬FVC ϭ Ϫ31 Ϯ 11%)-and high-dose ATP (⌬FVC Ϫ25 Ϯ 11%; P ϭ 0.70 low vs. high dose). Collectively, our findings indicate a potential modest role for NO and PGs in the vasodilatory response to exogenous ATP in the human forearm that does not appear to be dose or timing dependent; however, this is dependent on the method for assessing forearm vascular responses. Importantly, the majority of ATP-mediated vasodilation is independent of these putative endothelium-dependent pathways in humans. endothelium dependence; purine; adenosine triphosphate ADENOSINE TRIPHOSPHATE (ATP) is an important nucleotide with various functions including diverse effects on the cardiovascular system (3). With respect to the control of vascular tone, ATP can be released as a cotransmitter with norepinephrine from sympathetic nerve endings, bind to P 2X receptors on smooth muscle cells, and evoke subsequent vasoconstriction (4). In contrast, circulating ATP can bind to P 2Y receptors on the vascular endothelium, which results in vasodilation, the magnitude of which can reach levels observed during exercise in the peripheral circulation (3, 16). Accumulati...
