Systemic Hypoxia Elevates Skeletal Muscle Interstitial Adenosine Levels in Humans

MacLean, D. A.; Sinoway, Lawrence I.; Leuenberger, Urs A.

doi:10.1161/01.cir.98.19.1990

Cited by 71 publications

(53 citation statements)

References 19 publications

(23 reference statements)

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“…Because hypoxia raises sympathetic vasoconstrictor nerve traffic and norepinephrine spillover (14,31), vasodilation results from release of systemic or local vasodilator factors. In agreement with studies in rodents (22,24,26), it has been reported that nitric oxide (NO) (7,9,16,35) and adenosine (15,18) contribute to hypoxiainduced vasodilation in humans. In addition, some reports (6,35), but not others (27), support a role for an increase in circulating epinephrine, and one recent report (19) suggests that vasodilator prostaglandins also contribute to the skeletal muscle vasodilation elicited by systemic hypoxia.…”

supporting

confidence: 80%

“…In a series of studies, Marshall and collaborators demonstrated that adenosine, NO, and vasodilator prostaglandins each contribute to the skeletal muscle vasodilation induced by hypoxia in rodents (20,24,26). In an extension of these studies in humans, NO (7,9,35) and adenosine (15,18,24) have also been shown to play a role in the hypoxia-induced vasodilation in humans. It has also been shown that vasodilation during hypoxia can result from reduction of nitrite to NO as a function of local PO 2 (10).…”

Section: Discussionmentioning

confidence: 98%

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Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans

Spilk

Herr

Sinoway

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Spilk S, Herr MD, Sinoway LI, Leuenberger UA. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans. Am J Physiol Heart Circ Physiol 305: H1639 -H1645, 2013. First published September 16, 2013 doi:10.1152/ajpheart.00073.2013.-Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O 2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N G -monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole ϩ L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial PO 2 ϳ37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole ϩ L-NMMA reduced (P Ͻ 0.05) forearm vascular conductance (FVC) by ϳ10% and ϳ18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 Ϯ 0.37 and 0.95 Ϯ 0.35 units in control and experimental forearms, respectively (P Ͻ 0.05). During hypoxia and fluconazole ϩ L-NMMA (trial 2), FVC increased by 2.32 Ϯ 0.51 and 0.72 Ϯ 0.22 units in control and experimental forearms, respectively (P Ͻ 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n ϭ 8) FVC increased by 1.51 Ϯ 0.46 and 0.45 Ϯ 0.32 units in control and experimental forearms, respectively (P Ͻ 0.05). These effects were not due to altered skin blood flow. We conclude that endotheliumderived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.hypoxia; vasodilation; endothelium-derived hyperpolarizing factor; fluconazole; nitric oxide UNDER BASAL CONDITIONS and during physiological stress, skeletal muscle blood flow is closely matched to metabolic demand. Accordingly, in healthy humans, systemic hypoxia is accompanied by skeletal muscle vasodilation, which serves to maintain O 2 homeostasis (20,27,29). Because hypoxia raises sympathetic vasoconstrictor nerve traffic and norepinephrine spillover (14, 31), vasodilation results from release of systemic or local vasodilator factors. In agreement with studies in rodents (22,24,26), it has been reported that nitric oxide (NO) (7,9,16,35) and adenosine (15, 18) contribute to hypoxiainduced vasodilation in humans. In addition, some reports (6, 35), but not others (27), support a role for an increase in circulating epinephrine, and one recent report (19) suggests that vasodilator prostaglandins also contribute to the skeletal muscle vasodilation elicited by systemic hypoxia. Thus multiple endogenous vasodilator mechanisms ...

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supporting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans

Spilk

Herr

Sinoway

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the brain, adenosine exerts an inhibitory tone and serves as an endogenous neuroprotective agent against ischemia-and seizure-induced neuronal injury (Rathbone et al, 1999;Latini and Pedata, 2001). In the skeletal muscle, adenosine functions as a locally produced regulator of muscle blood flow and plays a major protective role during systemic hypoxia (Hellsten et al, 1998;MacLean et al, 1998). Our quantitative PCR results showed that hENT1 is highly expressed in both human brain and skeletal muscle (Fig.…”

Section: Discussionmentioning

confidence: 81%

Adenosine Transport by Plasma Membrane Monoamine Transporter: Reinvestigation and Comparison with Organic Cations

et al. 2010

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ABSTRACT:The plasma membrane monoamine transporter (PMAT) belongs to the equilibrative nucleoside transporter family (solute carrier 29) and was alternatively named equilibrative nucleoside transporter 4. Previous studies from our laboratory characterized PMAT as a polyspecific organic cation transporter that minimally interacts with nucleosides. Recently, PMAT-mediated uptake of adenosine (a purine nucleoside) was reported, and the transporter was proposed to function as a dual nucleoside/organic cation transporter. To clarify the substrate specificity of PMAT, we comprehensively analyzed the transport activity of human PMAT toward nucleosides, nucleobases, and organic cations in heterologous expression systems under well controlled conditions. Among 12 naturally occurring nucleosides and nucleobases, only adenosine was significantly transported by PMAT.PMAT-mediated adenosine transport is saturable, pH-dependent, and membrane-potential sensitive. Under both neutral (pH 7.4) and acidic (pH 6.6) conditions, adenosine is transported by PMAT at an efficiency (V max /K m ) at least 10-fold lower than that of the organic cation substrates 1-methyl-4-phenylpyridinium and serotonin. PMATmediated adenosine uptake rate was significantly enhanced by an acidic extracellular pH. However, the effect of acidic pH was not adenosine-specific but was common to organic cation substrates as well. Our results demonstrated that although PMAT transports adenosine, the transporter kinetically prefers organic cation substrates. Functionally, PMAT should be viewed as a polyspecific organic cation transporter rather than an archetypical nucleoside transporter.

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“…Adenosine, a potent vasodilator, has been demonstrated to increase in skeletal muscle and contribute to vasodilation in response to systemic hypoxia (18,19). Endothelium-derived prostaglandins also have a clear role in modulating skeletal muscle vasodilation in response to hypoxia (20).…”

Section: Discussionmentioning

confidence: 99%

Evidence of impaired hypoxic vasodilation after intermediate-duration hypoxic exposure in humans

Gilmartin¹,

Tamisier²,

Anand³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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-Systemic hemodynamics, including forearm blood flow and ventilatory parameters, were evaluated in 21 subjects before and after exposure to 8 h of poikilocapnic hypoxia. To evaluate the role of sympathetic nervous system activation in the changes, in 10 of these subjects, we measured muscle sympathetic nerve activity (MSNA) before and after exposure, and the remaining 11 subjects received intra-arterial phentolamine infusion in the brachial artery to define vascular tone in the absence of sympathetically mediated vasoconstriction. Short-term ventilatory acclimatization occurred as evidenced by a decrease in resting PCO 2 (from 42 Ϯ 1.4 to 37 Ϯ 0.96 mmHg) and by an increase in the slope of the ventilatory response to acute hypoxia [from 0.7 Ϯ 0.1 to 1.2 Ϯ 0.2 l ⅐ min Ϫ1 ⅐ %SpO 2 (blood O2 saturation from pulse oximetry)] after exposure. Subjects demonstrated a significant increase in resting heart rate (from 61 Ϯ 2 to 65 Ϯ 2 beats/min) and diastolic blood pressure (from 64.8 Ϯ 2.7 to 70.4 Ϯ 2.0 mmHg). MSNA did not change significantly after exposure, although there was a trend toward a decrease in burst frequency (from 19.8 Ϯ 4.1 to 14.3 Ϯ 1.2 bursts/min). Forearm vascular resistance showed a significant decrease after termination of exposure (from 37.7 Ϯ 3.6 to 27.6 Ϯ 2.7 mmHg ⅐ ml Ϫ1 ⅐ min ⅐ 100 g tissue, P Ͻ 0.05). Initially, progressive isocapnic hypoxia elicited significant vasodilation, but after 8 h of poikilocapnic hypoxic exposure, the acute challenge failed to change forearm vascular resistance. Local ␣-blockade with phentolamine restored the vasodilatory response to acute hypoxia in the postexposure setting.acclimatization; muscle sympathetic nerve activity; vascular resistance EXTENDED EXPOSURES TO HYPOXIA are associated with increases in ventilation that persist after termination of the exposure. This increase in ventilation, termed hypoxic acclimatization, is attributed primarily to an increase in peripheral chemosensitivity (2,5). Acclimatization has been demonstrated to occur following exposures as brief as 8 h in human subjects (15,16). Because afferent traffic from the peripheral chemoreceptor partly determines sympathetic activity, we postulated that a hypoxic exposure of sufficient duration to induce ventilatory acclimatization also would induce sustained sympathoexcitation that would persist after termination of the hypoxic exposure. To test this hypothesis, we assessed muscle sympathetic nerve activity (MSNA) in normal volunteers before and after an 8-h exposure to hypoxia previously shown to produce ventilatory acclimatization. Because hypoxic exposure also stimulates release of endogenous vasodilators that may persist after the exposure, we further sought to define vascular tone in our subjects by assessing vascular resistance both with and without local blockade of sympathetic input with the use of nonspecific ␣-blockade with local arterial infusion of phentolamine.The goals of this study, therefore, were 1) to define the changes in MSNA associated with ventilatory acclimatization followi...

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Systemic Hypoxia Elevates Skeletal Muscle Interstitial Adenosine Levels in Humans

Cited by 71 publications

References 19 publications

Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans

Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans

Adenosine Transport by Plasma Membrane Monoamine Transporter: Reinvestigation and Comparison with Organic Cations

Evidence of impaired hypoxic vasodilation after intermediate-duration hypoxic exposure in humans

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