Has the phoenix risen?

Both static and dynamic exercise increase the activity of postganglionic sympathetic fibres innervating the vasculature of limb muscles. This increase in sympathetic activity is believed to serve two purposes. The first is to increase perfusion pressure in the vessels supplying exercising muscles, and the second is to counter excessive vasodilatation in muscles where metabolism is greatly increased over resting levels. Two neural mechanisms have been investigated as the cause of the exercise-induced increase in muscle sympathetic nerve activity (MSNA). The first is the exercise pressor reflex (Mitchell et al. 1983), which arises from both mechanical and metabolic stimuli in the contracting muscles. The second is central command, which is defined as the parallel activation of motor, autonomic and ventilatory neuronal circuits in the brainstem. Central command does not depend on sensory input from exercising muscles (Eldridge et al. 1985).

The exercise pressor reflex, evoked by metabolic stimuli, is believed to be the primary neural mechanism causing the increase in MSNA during muscular work. Central command, while responsible for much of the cardioaccelerator and ventilatory responses to exercise, does not appear to increase MSNA unless the intensity of the exercise is near maximal. Alam & Smirk (1937) were the first to demonstrate that a metabolic stimulus can evoke the exercise pressor reflex. They showed that the pressor response to leg exercise was maintained after the end of the exercise period if the circulation to the previously contracting leg was occluded. Many other investigators have replicated this finding, and, consequently, it is a well-accepted fact that trapping metabolites in previously exercising muscles evokes a pressor response; this effect, which is a constituent of the exercise pressor reflex, has been named the muscle metaboreflex or muscle chemoreflex; the two names are used interchangeably (Rowell & O'Leary, 1990).

The nature of the metabolic stimulus evoking the muscle metaboreflex is controversial and is the focus of this perspective. Particular attention has been paid to the role played by lactic acid as this stimulus. There is a substantial body of evidence in animals that hydrogen ions stimulate thin fibre afferents from a variety of tissues including skeletal muscle, skin and the heart. Nevertheless, the ultimate test for lactic acid being the metabolite that evokes the muscle metaboreflex must be performed in humans.

Pryor et al. (1990) found that patients with a myophosphorylase deficiency (i.e. McArdle's disease) did not increase their MSNA when performing static handgrip, whereas healthy subjects did. McArdle's patients lack the myophosphorylase enzyme that breaks down glycogen and therefore produce little if any lactic acid when they exercise. Pryor et al. (1990) found that patients with myophosphorylase deficiency displayed increases in MSNA in response to standard tests of sympathetic function, such as the Valsalva manoeuvre and the cold pressor test; consequently, their inability to increase MSNA in response to handgrip was not caused by generalized sympathetic failure. The report by Pryor et al. (1990) was the first to demonstrate in humans that lactic acid played an important, if not crucial role, in evoking the muscle metaboreflex.

Vissing et al. (1998, 2001) subsequently challenged the concept that lactic acid evoked the muscle metaboreflex. These investigators reported that arm flexion performed by McArdle's patients increased MSNA even though the exercising muscles did not acidify. Moreover, post-exercise circulatory occlusion maintained this increase in MSNA. The conclusions drawn by Vissing et al. (1998, 2001) contrasted with those drawn by Pryor et al. (1990). In their final sentence, Vissing et al. (2001) stated ‘the hypothesis of muscle acidification in exercise as a prerequisite for sympathoexcitation during exercise should be abandoned’.

A statement such as this is both provocative and premature, especially considering the fact that it is based on findings from one laboratory. Nevertheless, such statements do have a beneficial effect, namely that they stimulate further research. This beneficial effect is seen in an article in the current issue of The Journal of Physiology. In this article Fadel et al. reexamined the role played by lactic acid in evoking the muscle metaboreflex in McArdle's patients. In addition to replicating the report by Pryor et al. (1990), Fadel et al. offered a partial explanation for the findings by Vissing et al. (1998, 2001). Fadel et al. believe that the magnitude of the metaboreflex-induced increase in MSNA is highly variable in healthy subjects, and consequently, its true magnitude can be underestimated by the small sample sizes used by Vissing et al. (1998, 2001). To control for this possibility, Fadel et al. paired each McArdle's patient with three healthy subjects. This pairing revealed a substantial MSNA response to the muscle metaboreflex in healthy subjects. Most importantly, the metaboreflex-induced MSNA response in healthy subjects dwarfed the MSNA response in McArdle's patients.

This explanation does not address the fact that Vissing et al. (1998, 2001) found that the MSNA component of the muscle metaboreflex was substantial in McArdle's patients, whereas Fadel et al. (2003) and Pryor et al. (1990) found that this component was almost non-existent. This difference does not appear to be reconcilable. All that can be offered is a plea for more research from other laboratories to resolve this important issue.

One interpretation of the findings of Fadel et al. is that lactic acid must be present to evoke the muscle metaboreflex. This lack of redundancy might appear as counter-intuitive because the best design for a system would be for it to respond to several stimuli in case one is not present. Maybe this lack of redundancy is specific to patients with McArdle's disease. In any event the issue of redundant stimuli needs to be investigated further.

Although these contrasting findings are confusing and appear to have no apparent resolution, two things are clear. First, the experiments performed in humans with rare diseases demonstrate the power of integrative physiology. Second, abandoning the muscle acidification hypothesis is premature; the hypothesis needs further testing. Perhaps the phoenix has risen?