Neural control of the circulation: exercise

The initial findings of Krogh and Lindhard in humans, in which they linked the 1886 work of Zuntz and Geppert on the 'exercise pressor reflex' (EPR) and the 1893 work of Johannson on 'central command' (CC), developed into a major field of integrative physiology research, subsequently identified as 'the neural control of the circulation'. Krogh and Lindhard's early investigations occurred between 1909 and 1930 and identified the presence of a central nervous system-initiated neural signal, or CC, that increased heart rate and cardiac output at the beginning of exercise. It was not until 1937 when Alam and Smirk measured blood pressure using auscultation during exercise and recovery that the presence of a blood pressure-raising reflex initiated within the exercising skeletal muscle, or EPR, was established to be operational in humans. The afferent signal arising from the exercising skeletal muscle was concluded to be a result of sensing one or more chemicals that were trapped within an exercised limb, which in this case was produced by inflation of a cuff around the arm during exercise and recovery. Subsequently, in 1941, Schmidt and Comroe published a review of a number of investigations into exercise hyperpnoea and concluded that the increase in ventilation was due to neural reflexes arising from the contracting muscle. In 1943, they then went on to confirm that the exercising muscle was indeed the source of the exercise-induced increase in ventilation. In the 1950s, Kao and others developed a cross-circulation technique between pentobarbital-anaesthetized dogs, in which the hindlimbs of one dog were exercised by electrical stimulation of the spinal motor nerves serving limb muscles. In 1970, Coote and others refined this neurophysiological stimulation technique to enable the selective stimulation of the distal ends of the cut ventral roots of the spinal nerves to the hindlimbs and, therefore, eliminate any possibility for retrograde nerve traffic. In this physiological preparation, stimulation of the cut ventral roots increased blood pressure and heart rate, whereas sectioning of the dorsal roots abolished this response. Subsequently, in the next year the increases in heart rate and blood pressure were demonstrated by McCloskey and Mitchell, using differential anodal and anaesthetic (lidocaine) blocking techniques of the afferent nerves arising from the stimulated skeletal muscle, to be in response to the activation of type III and IV afferent nerves. Concurrent with this previous work, Mitchell again joined forces with McCloskey and Guy Goodwin as co-investigators to examine the role of CC in the response of the circulation and ventilation to exercise in humans. These experiments conclusively identified a role for CC in regulating the heart rate, blood pressure and ventilation response to muscle contraction. Based upon this work, a vast amount of fundamental information involved in the neural control of the circulation has been identified from investigations performed after 1972 and continuing today. A number of comprehensive reviews published in 1981 (Mitchell, 1981), 1990 (Mitchell, 1990) and 1996 (Kaufman & Forster, 1996; Waldrop et al. 1996) identify that activation of either CC or EPR involves central and peripheral afferent neural inputs into central neural networks that process the information and result in efferent neural signals regulating the appropriate cardiorespiratory responses that occur during static and dynamic exercise (Rowell et al. 1996). In a 2006 Themed Issue on the Neural Control of the Circulation During Exercise published in Experimental Physiology (Exp Physiol 91, 25–119, 2006), an additional body of work identifying the influence of the arterial and cardiopulmonary baroreflexes on the gestalt of the neural control of the circulation was presented. The publications that make up the symposium proceedings are representative of the presentations provided by the speakers at the 40 year celebration symposium of the collaborative work of Goodwin, McCloskey and Mitchell. The symposium celebrates the landmark investigations performed during Mitchell's time as a Visiting Senior Scientist at the University Laboratory of Physiology at Oxford University in 1970–1971. The symposium, entitled The Neural Control of the Circulation during Exercise, was presented at the Annual Physiological Society meeting at Oxford University in July, 2011. All but one of the presenters and major authors has, at some time in their careers, worked as investigative collaborators with Mitchell. However, all of the presenters' careers have been influenced directly, or indirectly, by Mitchell's continuing 56 year involvement in cardiovascular research. The article by Mitchell (2012) provides a personal historical background of the investigations he performed in Oxford and identifies some of the influential individuals of Oxford University whom he encountered. He also indicates that investigations that he and many others have performed since the initial work have expanded to include arterial baroreflex control of blood pressure. Furthermore, he identifies that the focus of current research has expanded into investigating the pathophysiological responses to exercise evident in the spontaneously hypertensive rat by Smith (2006) and the rat model of heart failure by Smith et al. (2006). In the article by Matsukawa (2012), he provides his team's evidence from animal preparations that CC is generated within the diencephalon and mesencephalon, but appears to be initiated by descending signals from the cortical structures. In addition, their work has begun to unravel the neural circuits within the brain that must enable the interaction that is evident between the CC and EPR in providing the in vivo physiological responses during exercise. In deference to the integrative physiologist's primary ambition of translating the cellular and molecular biological mechanisms identified in vitro to humans, animal experimentation and human functional imaging, invasive measures and selective pharmacological blockade have been the main avenues of experimental manipulation. The article by Basnayake et al. (2012) presents the results of an exciting collaboration of neurosurgeons and neurophysiologists employing techniques of functional neurosurgery in humans. Their findings identify that the periaqueductal grey may be the major site of neural integration for providing effective cardiovascular responses to exercise. In the article by Kaufman (2012), he provides a detailed summary of his group's recent work. In their experiments, they used the decerebrate cat model performing fictive treadmill walking and identified that the group III mechanically sensitive muscle afferents respond in phase with muscle contraction and the group IV metabolically sensitive muscle afferents respond irregularly with the step cycle. Furthermore, they identified specific purinergic (P) 2 channels and acid-sensitive ion channels associated with group III and group IV muscle afferents. In the article by Secher & Amman (2012), they highlight the use of regional anaesthesia, neuromuscular blockade of healthy humans and patients with spinal injury in selectively blocking afferent information emanating from the exercising and respiratory muscles. In the article by Fadel & Raven (2012), they review the findings of a number of recent experiments involving exercising humans that identify the role of central blood volume in establishing the operating point of the arterial baroreflex by acting as a modulator of the primary inputs of CC and EPR in the active resetting of the arterial baroreflexes. In summary (Fig. 1), the proceedings of the symposium report on the present human and animal investigations into the unanswered integrative physiological questions raised by the historic work of many other investigators into the activation of CC and the EPR during exercise. Furthermore, the proceedings provide a summary of evidence identifying the role of the arterial and cardiopulmonary baroreflexes in modulating the amount of CC and EPR activation of sympathetic and parasympathetic activity around a given operating point. A schematic representation of the neural control of the circulation '1 & 2' outline the neural pathways involved in the influence of central command on the nucleus tractus solitarii (NTS) discussed by Matsukawa (2012) and Basnayake et al. (2012). '3 & 4' outline the neural pathways involved in the influence of the exercise pressor reflex on the NTS discussed by Kaufman (2012) and Secher & Amann (2012). '5' outlines the neural pathways involved in the influence of the arterial and cardiopulmonary baroreflex on the NTS discussed by Fadel and Raven (2012).