title: Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins.
abstract: 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 = 18), a dose-response curve to intrabrachial infusion of ATP was performed before and after both single and combined inhibition of NO synthase [N(G)-monomethyl-L-arginine (L-NMMA)] and 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 = 0.22-0.99). In protocol 2 (n = 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 = 8)- and high-dose (n = 8) ATP for 5 min evoked a significant increase in FVC above baseline (low = 198 ± 24%; high = 706 ± 79%). Infusion of L-NMMA and ketorolac together reduced steady-state FVC during both low- and high-dose ATP (P < 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 (ΔFVC = -31 ± 11%)- and high-dose ATP (ΔFVC -25 ± 11%; P = 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.
authors.affiliation: Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Vascular Physiology Research Group, Department of Biomedical Sciences, Colorado State University, Fort Collins 80523-1582, USA.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Crecelius
authors.forename: Brett S
authors.initials: BS
authors.lastname: Kirby
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Richards
authors.forename: Leora J
authors.initials: LJ
authors.lastname: Garcia
authors.forename: Wyatt F
authors.initials: WF
authors.lastname: Voyles
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Larson
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Luckasen
authors.forename: Frank A
authors.initials: FA
authors.lastname: Dinenno
mesh_terms: D015502:Absorptiometry, Photon; D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000328:Adult; D001823:Body Composition; D001916:Brachial Artery / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D020911:Ketorolac Tromethamine / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D011453:Prostaglandins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D020911:Ketorolac Tromethamine; D000255:Adenosine Triphosphate; D052248:Nitric Oxide Synthase Type I