The Journal of Physiology and the odyssey of ‘neural control of the circulation during exercise’

As an initiative to celebrate The Journal of Physiology’s 600th volume, ground-breaking discoveries are being recognized and placed in perspective for their contributions to the advancement of particular subfields of physiology. Herein we, rather than singling out a particular paper, praise The Journal of Physiology as the host for the odyssey of ‘neural control of the circulation during exercise,’ a series of landmark studies that decrypted the dialogue between the brain and the contracting skeletal muscle and unravelled the mechanisms involved in perhaps the most universal observations in physiology: the increase in heart rate (HR) and blood pressure (BP) during exercise. This perspective then portrays the evidence that, through a ‘bedside-to-bench and back again’ translational research paradigm, grounded the hypothesis that central and peripheral mechanisms are essential to these adjustments and paved the way for the contemporary and comprehensive understanding of exercise cardiovascular physiology. The odyssey was initiated a little more than a decade after the founding of The Journal of Physiology when two distinctive control mechanisms, one originating in the brain and the other in the skeletal muscle, emerged from an animal model as regulators of the cardiovascular response to exercise (Johansson, 1893). In a subsequent study published in The Journal of Physiology, Nobel prize laureate Professor August Krogh and his associate Professor Johannes Lindhard translated and proposed the existence of the centrally generated regulatory signal in humans (Krogh & Lindhard, 1913). They documented an immediate rise in ventilation (V̇E) when individuals transited from rest to exercise in a bicycle ergometer devised by Krogh himself. Limited by the absence of technology, Krogh and Lindhard counted on the kindness of Miss Florence Buchanan to carry out parallel experiments in Oxford using the electrocardiogram to display that HR increased from the first beat that occurred after the onset of exercise on a stationary tricycle. The rapidity of the cardiorespiratory adjustments to exercise led them to theorise that ‘irradiation’ of impulses from the motor cortex would act through the respiratory and cardiovascular centres to provoke the immediate increases in V̇E and HR. This insightful assumption formed the basis for the following accumulating evidence that, through a decorticate animal model of ‘fictive’ locomotion, the use of brain imaging techniques (Williamson et al., 1997), or, more recently, the direct recording of local field potentials (Green et al., 2007) or stimulation (Thornton et al., 2002) of several human cortical nuclei, provided support for the existence of this centrally originated mechanism responsible for the cardiovascular adjustments to exercise. Krogh and Lindhard (1917) later recognized that the contribution of a peripherally originated mechanism to the cardiovascular adjustments would occur as the exercise progresses, since electrically-induced muscle contractions evoked delayed tachycardia. This assumption was also supported by evidence from Oxford that the pressor response and the exercise tachycardia were proportional to the increments in muscular work and metabolism (Paterson, 1928). Both studies hypothesized that a chemical stimulus would be involved; however, the prevailing view that the activation of sensory fibres by metabolites released from the contracting skeletal muscles reflexively contributes to cardiovascular adjustments to exercise gained attention only after the study by M. Alam and Sir F. Horace Smirk (Alam & Smirk, 1937). The observation that BP remained elevated after the cessation of handgrip trials if the forearm circulation was arrested (by inflating a cuff on the upper exercising arm) led them to deduce that the pressor response was a consequence of a reflex activated by the trap and accumulation of muscle metabolites with a resulting passage of nerve impulses out of the contracting muscle. Remarkably, the methodological approach adopted in this investigation has been named post-exercise muscle ischemia and consistently applied over the following eighty years to examine the mechanistic nature of this reflex that emanates from the contracting skeletal muscle. Despite the solid evidence of the reflex nature of the pressor response to exercise in humans, the existence of the mechanism originating peripherally was challenged as succeeding animal experimentation reported a depressor effect to skeletal muscle contraction. Aware of potential aspects that had distorted the appropriate afferent input arising from contracting muscles and the resulting pressor response, Professor John H. Coote, at that time a lecturer at the University of Birmingham, published two papers in The Journal of Physiology that provided the neurophysiological foundation of the muscle pressor reflex. Together with J.F. Perez-Gonzalez, Coote demonstrated that the direct electrical stimulation of high threshold group III and group IV afferent fibres excited sympathetic neurones and elicited pressor responses (Coote & Perez-Gonzalez, 1970). A year later, Coote and colleagues also showed that cutting the dorsal root from the cat gastrocnemius abolished the increase in blood pressure evoked by the electrical ventral root stimulation-induced contraction of the hindlimb muscles (Coote et al., 1971). The experimental approach and insights from these experiments worked as inspiration for what is perhaps the most classic and recognized investigation in the field (McCloskey & Mitchell, 1972), which constituted the kick-off of the contemporary era of the ‘neural control of the circulation during exercise’ odyssey. In their classic study, DI McCloskey and JH Mitchell showed that, rather than being a consequence of activation of the large myelinated sensory fibres, the pressor and chronotropic responses to ventral root stimulation-induced skeletal muscle contraction were reflexively evoked by activating thinly myelinated and unmyelinated group III and IV afferents, as only local anaesthetic deposition, but not anodal blockade of the dorsal roots, abolished these adjustments (McCloskey & Mitchell, 1972). Since then, under the leadership of Mitchell and others, efforts have been dedicated to determining (1) the stimuli that activate specific receptors/channels located in the sensory fibre terminals, (2) the pathways and neurotransmitters in the spinal cord (Wilson et al., 1993) and brainstem, (3) how the afferent information interacts with other reflexogenic responses, and, most importantly, (4) the role of the muscle reflex in the disturbed haemodynamic changes observed in pre-clinical (Smith et al., 2006) and human models of chronic diseases. Not surprisingly, Mitchells' work named both the skeletal muscle and cortical irradiation mechanisms as exercise pressor reflex and central command, respectively, with last being termed after one of the most elegant experiments in the field. In association with GM Goodwin and DI McCloskey, applying vibration to the biceps tendon to decrease and increase central command's contribution to develop and maintain tension during biceps or triceps contraction, respectively, Mitchell provided evidence that the magnitude of the cardiovascular adjustments depends on the level of descending cortex signals during voluntary exercise (Goodwin et al., 1972). Together, these landmark studies built the foundation for our contemporary understanding of the mechanisms responsible for cardiovascular adjustments during exercise, and their impact is evidenced by impressive metrics such as the number of citations and cited half-life. They also constitute part of the legacy of visionary and influential investigators who, even if no longer amongst us, continue to inspire generations of scientists and help to advance physiological knowledge. Why these giants chose The Journal of Physiology as the venue for their contributions to unravelling this odyssey cannot be known, but it may be because, as Mitchell once said, ‘there are many journals related to physiology, but there is only one that is THE Journal of Physiology.’ Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. I.A.F. was involved with the conception of this editorial and drafted its first version. A.L.T. and N.H.S. revised the article critically for important intellectual content. None. We thank Professor Kim E Barrett for the insightful comments and language review.

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