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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 [NG-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. [ABSTRACT FROM AUTHOR]

Acute ascorbic acid (AA) administration increases muscle blood flow during dynamic exercise in older adults, and this is associated with improved endothelium-dependent vasodilation. We directly tested the hypothesis that increase in muscle blood flow during AA administration is mediated via endothelium-derived vasodilators nitric oxide (NO) and prostaglandins (PGs). In 14 healthy older adults (64 ± 3 yr), we measured forearm blood flow (FBF; Doppler ultrasound) during rhythmic handgrip exercise at 10% maximum voluntary contraction. After 5-min steady-state exercise with saline, AA was infused via brachial artery catheter for 10 min during continued exercise, and this increased FBF ~25% from 132 ± 16 to 165 ± 20 ml/min (P < 0.05). AA was infused for the remainder of the study. Next, subjects performed a 15-min exercise bout in which AA + saline was infused for 5 min, followed by 5 min of the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and then 5 min of the cyclooxygenase inhibitor ketorolac (group 1). The order of inhibition was reversed in eight subjects (group 2). In group 1, independent NOS inhibition reduced steady-state FBF by ~20% (P < 0.05), and subsequent PG inhibition had no impact on FBF (Δ 3 ± 5%). Similarly, in group 2, independent PG inhibition had little effect on FBF (Δ -4 ± 4%), whereas subsequent NO inhibition significantly decreased FBF by ~20% (P < 0.05). In a subgroup of five subjects, we inhibited NO and PG synthesis before AA administration. In these subjects, there was a minimal nonsignificant improvement in FBF with AA infusion (Δ 7 ± 3%; P = nonsignificant vs. zero). Together, our data indicate that the increase in muscle blood flow during dynamic exercise with acute AA administration in older adults is mediated primarily via an increase in the bioavailability of NO derived from the NOS pathway. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that aging is associated with an impaired contraction-induced rapid vasodilation in healthy adults. We reasoned that employing single contractions of a small muscle mass would allow us to isolate the local rapid vasodilatory responses independent of systemic hemodynamic and sympathetic neural influences on forearm hemodynamics. We measured forearm blood flow (Doppler ultrasound) and arterial blood pressure (Finapres) on a beat-by-beat basis and calculated the changes in forearm vascular conductance (L~FVC) in response to forearm contractions in 18 young (24 ± 1 yr) and 13 older (62 ± 2 yr) healthy subjects. Single, 1-s dynamic forearm contractions were performed with the experimental arm slightly above heart level at 5, 10, 20, and 40% of the subjects' maximal voluntary contraction (MVC) in random order. In general, muscle contractions evoked a rapid increase in FVC that reached a peak within approximately four to five cardiac cycles postcontraction in both age groups. At 5% MVC, there were no significant age-related differences in contraction-induced forearm vasodilation. However, the peak vasodilatory responses were impaired -40-45% in older adults at 10, 20, and 40% MVC, as were the total vasodilatory responses (area under curve -40-50%; all P < 0.05). Additionally, the immediate vasodilation (first cardiac cycle postcontraction) for the 20% and 40% MVC trials was also impaired -50% with age (P < 0.05). There were no significant age-group differences in MVC or forearm fat-free mass, and these variables were not correlated with local vasodilation within a given exercise intensity. Under the experimental conditions employed, the blunted responses with age reflect impaired local contraction-induced rapid vasodilation. [ABSTRACT FROM AUTHOR]