Role of adenosine in the sympathetic activation produced by isometric exercise in humans.

Abstract

Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96±25% (n = 6, P < 0.01) and MABP by 12±3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 ytg/ml forearm per min) blocked the increase in MSNA (92±15% vs. 28±6%, n = 7, P < 0.01) and MABP (38±6 vs. 27±4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans. (J. Clin. Invest.

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

“…These effects are thought to be involved in the hypotensive response to intravenously administered adenosine as observed in animals and anesthetized humans. The indirect effects are mediated by adenosine-induced stimulation of afferent nerves, including renal (37,38) and myocardial afferent nerves (39a), carotid and aortic chemoreceptors (12,39), and forearm (muscle) afferent nerves (40). Stimulation of these afferents results in activation of the sympathetic nervous system and respiratory system (11,41) P values indicate level of significance for the difference between both curves (n = 10).…”

Post-exercise changes in blood pressure, heart rate and rate pressure product at different exercise intensities in normotensive humans

“…It is well understood that muscle metabolites and heat accumulation are directly related to exercise intensity, and sweating rate is greater during more intense exercise (29). In addition, the increased local muscle metabolites (30,31) and/or heat production (8) are also potential stimuli for the increased heart rate responses after moderate and high intensity exercise. Limitations.…”

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

“…Volkmann (1) proposed that the accumulation of chemical products of contraction in skeletal muscle somehow signals the brain of a mismatch between muscle blood flow and metabolism and evokes compensatory neurocirculatory responses to minimize this perfusion mismatch. There now is unequivocal evidence that metabolic products of contraction (such as H ϩ ) activate chemically sensitive skeletal muscle afferents that reflexively increase efferent-sympathetic vasoconstrictor discharge (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). This reflex mechanism (termed the "muscle metaboreflex") has been shown to trigger parallel sympathetic activation in resting and exercising human skeletal muscle (16), but the resultant effect of this reflex-sympathetic activation on muscle blood flow and oxygenation remains poorly understood.…”