Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults

Abstract

Crecelius AR, Kirby BS, Voyles WF, Dinenno FA. Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults. Am J Physiol Heart Circ Physiol 299: H1633-H1641, 2010. First published September 3, 2010; doi:10.1152/ajpheart.00614.2010.-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 Ϯ 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 ϳ25% from 132 Ϯ 16 to 165 Ϯ 20 ml/min (P Ͻ 0.05). AA was infused for the remainder of the study. Next, subjects performed a 15-min exercise bout in which AA ϩ saline was infused for 5 min, followed by 5 min of the nitric oxide synthase (NOS) inhibitor N G -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 ϳ20% (P Ͻ 0.05), and subsequent PG inhibition had no impact on FBF (⌬ 3 Ϯ 5%). Similarly, in group 2, independent PG inhibition had little effect on FBF (⌬ Ϫ4 Ϯ 4%), whereas subsequent NO inhibition significantly decreased FBF by ϳ20% (P Ͻ 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 (⌬ 7 Ϯ 3%; P ϭ 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. blood flow; aging; muscle contractions THE REGULATION OF BLOOD FLOW and oxygen delivery to contracting muscle is a complex response that involves mechanical factors, the sympathetic nervous system, and local metabolic and endothelium-derived substances that can influence vascular tone (28). In aging humans, an imbalance occurs in these regulatory mechanisms that typically results in impaired vasodilation and attenuated muscle blood flow during exercise (17,19,25,26). Investigators have hypothesized that impaired endothelial vasodilator function contributes to the age-related impairment in muscle blood flow during exercise (8,27). Recently, our laboratory demonstrated (17) that improving endothelium-dependent vasodilation via the potent antioxidant ascorbic acid also improved muscle blood flow during rhythmic handgrip exercise in older adults, providing the...

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

“…Interestingly, the magnitude of increase in femoral vascular conductance was similar to that demonstrated previously in healthy, older individuals following a similar intravenous AO infusion (20). AO has been documented to activate endothelial nitric oxide synthase (25), and coinfusion of AO and a nitric oxide synthase inhibitor negates the ability of AO to improve blood flow and vascular conductance (14). Thus, in the current study, intravenous infusion of AO may have improved nitric oxide bioavailability, perhaps by both reducing oxidative stress and promoting nitric oxide production by nitric oxide synthase, which resulted in a reduction in total peripheral resistance, leading to reduced MAP and improved femoral vascular conductance.…”

“…In addition, high-dose AO infusion has been documented to improve resting (20) and exercising (14,23) skeletal muscle blood flow in healthy older individuals. Improving limb blood flow, and possibly oxygen delivery, has the potential to attenuate the rate of development of peripheral muscle fatigue (3).…”

Mechanisms of ATP-mediated vasodilation in humans: modest role for nitric oxide and vasodilating prostaglandins

“…All subjects were sedentary to moderately active, nonsmokers, nonobese, normotensive (resting blood pressure Ͻ140/90 mmHg), and not taking any medications. Studies were performed after a 4-h fast and 24-h abstention from caffeine and exercise with subjects in the supine position with the experimental arm abducted to 90°and slightly elevated above heart level on a tilt-adjustable table (5). Female subjects were studied during the early follicular phase of their menstrual cycle or placebo phase of oral contraceptive use to minimize any potential cardiovascular effects of sex-specific hormones.…”

“…The catheter was connected to a three-port connector as well as a pressure transducer for mean arterial pressure (MAP) measurement and continuously flushed at 3 ml/h with heparinized saline. The two side ports were used for drug infusions (5,20).…”

“…The Doppler shift frequency spectrum was analyzed via a Multigon 500V TCD (Multigon Industries, Mt. Vernon, NY) spectral analyzer from which mean velocity was determined as a weighted mean of the spectrum of Doppler shift frequencies (5). Brachial artery diameter measurements were made in duplex mode at end-diastole and during steady-state conditions in triplicate.…”