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Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions ( P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions ( P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans. NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and β-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min -1 ·100 mmHg -1 ; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise. NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.

Skeletal muscle blood flow is attenuated in aged humans performing dynamic exercise, which is due, in part, to impaired local vasodilatory mechanisms. Recent evidence suggests that folic acid improves cutaneous vasodilation during localized and whole body heating through nitric oxide-dependent mechanisms. However, it is unclear whether folic acid improves vasodilation in other vascular beds during conditions of increased metabolism (i.e., exercise). The purpose of this study was to test the hypothesis that folic acid ingestion improves skeletal muscle blood flow in aged adults performing graded handgrip and plantar flexion exercise via increased vascular conductance. Nine healthy, aged adults (two men and seven women; age: 68 ± 5 yr) performed graded handgrip and plantar flexion exercise before (control), 2 h after (acute, 5 mg), and after 6 wk (chronic, 5 mg/day) folic acid ingestion. Forearm (brachial artery) and leg (superficial femoral artery) blood velocity and diameter were measured via Duplex ultrasonography and used to calculate blood flow. Acute and chronic folic acid ingestion increased serum folate (both P < 0.05 vs. control). During handgrip exercise, acute and chronic folic acid ingestion increased forearm blood flow (both conditions P < 0.05 vs. control) and vascular conductance (both P < 0.05 vs. control). During plantar flexion exercise, acute and chronic folic acid ingestion increased leg blood flow (both P < 0.05 vs. control), but only acute folic acid ingestion increased vascular conductance ( P < 0.05 vs. control). Taken together, folic acid ingestion increases blood flow to active skeletal muscle primarily via improved local vasodilation in aged adults. NEW & NOTEWORTHY Our findings demonstrate that folic acid ingestion improves blood flow via enhanced vascular conductance in the exercising skeletal muscle of aged humans. These findings provide evidence for the therapeutic use of folic acid to improve skeletal muscle blood flow, and perhaps exercise and functional capacity, in human primary aging.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/folic-acid-and-exercise-hyperemia-in-aging/., (Copyright © 2017 the American Physiological Society.)

In humans, acute aerobic exercise elicits a sustained postexercise vasodilation within previously active skeletal muscle. This response is dependent on activation of histamine H 1 and H 2 receptors, but the source of intramuscular histamine remains unclear. We tested the hypothesis that interstitial histamine in skeletal muscle would be increased with exercise and would be dependent on de novo formation via the inducible enzyme histidine decarboxylase and/or mast cell degranulation. Subjects performed 1 h of unilateral dynamic knee-extension exercise or sham (seated rest). We measured the interstitial histamine concentration and local blood flow (ethanol washout) via skeletal muscle microdialysis of the vastus lateralis. In some probes, we infused either α-fluoromethylhistidine hydrochloride (α-FMH), a potent inhibitor of histidine decarboxylase, or histamine H 1 /H 2 -receptor blockers. We also measured interstitial tryptase concentrations, a biomarker of mast cell degranulation. Compared with preexercise, histamine was increased after exercise by a change (Δ) of 4.2 ± 1.8 ng/ml ( P < 0.05), but not when α-FMH was administered (Δ-0.3 ± 1.3 ng/ml, P = 0.9). Likewise, local blood flow after exercise was reduced to preexercise levels by both α-FMH and H 1 /H 2 blockade. In addition, tryptase was elevated during exercise by Δ6.8 ± 1.1 ng/ml ( P < 0.05). Taken together, these data suggest that interstitial histamine in skeletal muscle increases with exercise and results from both de novo formation and mast cell degranulation. This suggests that exercise produces an anaphylactoid signal, which affects recovery, and may influence skeletal muscle blood flow during exercise. NEW & NOTEWORTHY Blood flow to previously active skeletal muscle remains elevated following an acute bout of aerobic exercise and is dependent on activation of histamine H 1 and H 2 receptors. The intramuscular source of histamine that drives this response to exercise has not been identified. Using intramuscular microdialysis in exercising humans, we show both mast cell degranulation and formation of histamine by histidine decarboxylase contributes to the histamine-mediated vasodilation that occurs following a bout of aerobic exercise., (Copyright © 2017 the American Physiological Society.)

New Findings: What is the central question of this study? Is exercise-induced oxidative stress the upstream exercise-related signalling mechanism that leads to sustained postexercise vasodilatation via activation of H1 and H2 histamine receptors? What is the main finding and its importance? Systemic administration of the antioxidant ascorbate inhibits sustained postexercise vasodilatation to the same extent as seen previously with H1 and H2 histamine receptor blockade following small muscle-mass exercise. However, ascorbate has a unique ability to catalyse the degradation of histamine. We also found that systemic infusion of the antioxidant N-acetylcysteine had no effect on sustained postexercise vasodilatation, suggesting that exercise-induced oxidative stress does not contribute to sustained postexercise vasodilatation. An acute bout of aerobic exercise elicits a sustained postexercise vasodilatation that is mediated by histamine H1 and H2 receptor activation. However, the upstream signalling pathway that leads to postexercise histamine receptor activation is unknown. We tested the hypothesis that the potent antioxidant ascorbate would inhibit this histaminergic vasodilatation following exercise. Subjects performed 1 h of unilateral dynamic knee extension at 60% of peak power in three conditions: (i) control; (ii) i.v. ascorbate infusion; and (iii) ascorbate infusion plus oral H1 /H2 histamine receptor blockade. Femoral artery blood flow was measured (using Doppler ultrasound) before exercise and for 2 h postexercise. Femoral vascular conductance was calculated as flow/pressure. Postexercise vascular conductance was greater for control conditions (3.4 ± 0.1 ml min(-1) mmHg(-1) ) compared with ascorbate (2.7 ± 0.1 ml min(-1) mmHg(-1) ; P < 0.05) and ascorbate plus H1 /H2 blockade (2.8 ± 0.1 ml min(-1) mmHg(-1) ; P < 0.05), which did not differ from one another (P = 0.9). Given that ascorbate may catalyse the degradation of histamine in vivo, we conducted a follow-up study, in which subjects performed exercise in two conditions: (i) control; and (ii) i.v. N-acetylcysteine infusion. Postexercise vascular conductance was similar for control (4.0 ± 0.1 ml min(-1) mmHg(-1) ) and N-acetylcysteine conditions (4.0 ± 0.1 ml min(-1) mmHg(-1) ; P = 0.8). Thus, the results in the initial study were due to the degradation of histamine in skeletal muscle by ascorbate, because the histaminergic vasodilatation was unaffected by N-acetylcysteine. Overall, exercise-induced oxidative stress does not appear to contribute to sustained postexercise vasodilatation., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)