Estimation of Skeletal Muscle Interstitial Adenosine During Forearm Dynamic Exercise in Humans

Abstract

Abstract-It has been proposed that adenosine is a metabolic signal that triggers activation of muscle afferents involved in the exercise pressor reflex. Furthermore, exogenous adenosine induces sympathetic activation that mimics the exercise pressor reflex, and blockade of adenosine receptors inhibits sympathetic activation induced by exercise. Thus, we hypothesize that adenosine is released locally by the muscle during exercise. We used microdialysis probes, placed in the flexor digitorium superficialis muscle, to estimate muscle interstitial adenosine levels in humans. We estimated resting in vivo muscle interstitial adenosine concentrations (0.292Ϯ0.058 mol/L, nϭ4) by perfusing increasing concentrations of adenosine to determine the gradient produced in the dialysate. Key Words: microdialysis Ⅲ adenosine Ⅲ muscle, skeletal Ⅲ exercise Ⅲ lactates M icrodialysis is a relatively new and minimally invasive technique that allows continuous sampling of extracellular substances of small molecular weight that will diffuse through the dialysis membrane. 1,2 It has been used to estimate interstitial concentrations of lactate, glucose, glutamate, norepinephrine, and adenosine, among others. 3 Over the last few years, the microdialysis technique has been introduced in human research, mostly to study skeletal muscle and subcutaneous metabolites. 4 We theorized that this technique would be particularly useful in the determination of extracellular concentrations of metabolites in which rapid cellular uptake and/or degradation constitutes a major limitation to their measurement by traditional techniques. Adenosine is one such metabolite.We have previously presented evidence supporting a role of adenosine in the triggering of the exercise pressor reflex, 5 the sympathetic activation resulting from isometric handgrip. We have found that exogenous adenosine induces sympathetic activation that mimics the exercise pressor reflex 6 and that blockade of adenosine receptors attenuates sympathetic activation induced by isometric exercise. 5 We postulate, therefore, that endogenous adenosine is released from skeletal muscle during ischemic exercise and activates muscle afferent fibers involved in the triggering of this reflex.It is difficult to test this hypothesis directly because of the challenges involved in measuring adenosine levels. Previous studies have used tissue biopsies to measure adenosine levels during ischemia. Whole tissue levels, however, do not discriminate between increases produced in the intracellular compartment or the interstitial space, the probable site of action. Attempts have also been made to measure adenosine levels in venous effluent. However, once outside the cell, adenosine is rapidly metabolized by adenosine deaminase and is reuptaken into cells via a very effective transporter. These processes explain the extremely short half-life of adenosine in human blood, reportedly Ͻ1 second. 7 Furthermore, the endothelium acts as an effective barrier to adenosine. 8 The microdialysis technique offers theoretical a...

Magnesium abnormalities of skeletal muscle in dermatomyositis and juvenile dermatomyositis

“…As previously shown, ATP is completely hydrolyzed under these conditions to adenine and adenosine, which subsequently exit from the muscle cells (1,6,36,37). ATP loss during moderate exercise results in fatigue and prolonged recovery, since it may take as long as several hours to resynthesize and restore intracellular ATP levels.…”

Adenosine A2A receptor modulation of juvenile female rat skeletal muscle microvessel permeability

“…In skeletal muscle, interstitial ADO concentration increases significantly during hypoxia (5), ischemia, and muscle contraction (8,22,23,34). For instance, in response to extensor exercise, the interstitial ADO in human vastus lateralis muscle increased fivefold from resting levels of 2.2 Ϯ 0.1 ϫ 10 Ϫ7 M at a work rate of 10 W (23).…”

“…During whole body dynamic exercise at maximal oxygen consumption, skeletal muscle receives 85-90% of cardiac output (11) compared with 20% at rest. Adenosine (ADO), a ubiquitous adenine nucleoside, was shown to be a key vasodilator in skeletal muscles under physiological and pathophysiological conditions including hypoxia (5), ischemia, and muscle contraction (8,22,23,34). Furthermore, ADO was found, from measures of permeability-surface area product (13), to increase skeletal muscle microvasculature blood-tissue exchange, an increase believed to be secondary to the increased exchange surface area downstream from the arterioles dilating in response to ADO (1,6,7,14).…”

Blockade of Nucleoside Transport Is Required for Delivery of Intraarterial Adenosine Into the Interstitium

“…2 The probe had a dialysis tubing size of 10ϫ0.5 mm (20 000 molecular mass cutoff) and was perfused continuously with saline at a rate of 2 L/min (perfusate) with a microinjection pump (CMA/102 Microdialysis Pump). The effluent (dialysate) was recovered with a fraction collector.…”

“…1,2 Adenosine is considered a retaliatory autacoid, whose main function is to protect tissues against ischemia-related injury. Many of its actions are indeed consistent with such a role.…”