Muscle afferent feedback during exercise: putting the pressure on flow

An increase in blood pressure occurs during exercise and has been suggested to be due, in part, via direct afferent signalling within the active skeletal muscle. Initial observations from Alam & Smirk (1937) indicated that elevations in blood pressure during exercise may arise from accumulation of metabolites within skeletal muscle, and suggested that this reflex may be designed so that the central nervous system (CNS) could aid in regulating the supply of blood to the active muscle. In this respect, blood flow to the active muscle could be increased via an augmented perfusion pressure. Recent evidence confirms the presence of metabolically sensitive (Type IV) afferent fibres in skeletal muscle tissue as well as mechanically sensitive (Type III) afferents that are suggested to be activated during muscle contraction and initiate this exercise pressor reflex (EPR) (Kaufman et al. 1983).

Following the original observations of an EPR, numerous studies have attempted to investigate the role that afferent signals originating from exercising muscle have on the cardiovascular response to exercise on both a systemic and local level. In humans, a variety of techniques have been employed; predominately limiting arterial inflow in order to augment metabolic afferent signalling, or administering local anesthetics to reduce afferent signalling to the CNS during voluntary contractions. Both methods are limited in that the former limits arterial inflow, complicating the assessment of vascular tone in response to the EPR and the latter augments central command. To date, these approaches have prevented the direct and continuous assessment of the exercise induced augmentation of mean arterial pressure (MAP) and its influence on skeletal muscle blood flow. As a result, it has been difficult to understand what contribution group III and IV skeletal muscle afferent feedback may have in regulating the cardiovascular response to exercise. Specifically, it remains unclear whether the blood pressure elevating reflex that occurs following stimulation of these muscle afferents serves to augment blood flow to muscle during exercise as Alam and Smirk first postulated.

In a recent article in The Journal of Physiology, Amann and colleagues utilized a novel technique to determine the cardiovascular response to graded knee-extensor exercise while limiting skeletal muscle afferent feedback (Amann et al. 2011). Intrathecal fentanyl, an opioid receptor agonist, was administered in order to limit afferent signalling of mechano- and metaboreceptors from the lower limbs during exercise. Amann and colleagues have previously utilized this pharmacological approach during high intensity cycling exercise and demonstrated that fentanyl does not decrease force generation, and thus should not augment central command (Amann et al. 2009). Further, this technique allows for the observation of cardiovascular responses without any physical impedance of blood flow to the active muscle. Therefore, the use of fentanyl minimizes specific confounding variables previously faced by other investigators and allows for a more precise observation of afferent signalling and its role in exercise hyperaemia.

Nine healthy male subjects had femoral artery and venous catheters placed in their exercising limb and performed knee extension exercise at 15, 30, 45 watts for 3 min each in both control condition and blockade (intrathecal fentanyl) conditions. At rest and at the end of each intensity of knee-extensor exercise, pulmonary and systemic cardiovascular variables, as well as local vascular responses were measured. In addition, local tissue oxygen consumption was calculated and sympathetic nervous system activity (SNA) during exercise was estimated via arterial and venous blood sampling (blood gas and noradrenaline (NA) concentrations). The authors hypothesized that limiting afferent feedback through the use of fentanyl would affect exercise responses by: (1) lowering heart rate (HR), stroke volume (SV), and cardiac output (CO); (2) decreasing exercise blood pressure; and(3) decreasing femoral artery blood flow (FBF). The findings from Amann and colleagues are largely in support of their hypotheses. Administration of fentanyl had no significant impact on any pulmonary, cardiovascular, NA concentration, or blood gas variables at rest. During exercise, there was a significant decline in HR, SV and CO that resulted in lower MAP and FBF following fentanyl administration. Importantly, although femoral vascular conductance (FVC) was lower in the fentanyl condition, a significantly lower MAP and FBF at each workload suggests that the reduction in FBF observed during fentanyl administration was clearly affected by an attenuation of perfusion pressure in the active skeletal muscle vasculature. Collectively, these findings from Amann et al. indicate that afferent feedback is crucial in raising MAP that subsequently increases muscle blood flow during moderate-intensity exercise in humans.

In addition to the main findings regarding local muscle blood flow and MAP, the authors made a number of other interesting observations. During afferent blockade with fentanyl, it is of interest that SV did not increase from rest as occurred in control conditions. It is possible that diminished afferent feedback and subsequent adrenergic tone to the heart lowered cardiac contractility as it is likely not due to decreased venous return given a lack of an effect of fentanyl on venous pressure. Additionally, with fentanyl, there was a blunted ventilatory response during exercise which led to lower arterial content and thereby contributed to lower leg oxygen delivery. To compensate for lower oxygen delivery and FBF, the arterial–venous oxygen difference was greater, yet oxygen consumption remained lower in the exercising blockade condition. These findings regarding changes in muscle blood flow, oxygen supply, and muscle metabolism at set workloads are potentially interesting areas for future study.

Although the investigators utilized a novel approach to more definitively identify the importance of skeletal muscle afferent feedback in regulating the EPR and cardiovascular response to exercise, it is likely that the role of afferent feedback may have been underestimated in the present study. If afferent signalling were the only input for increased SNA, we would presume that SNA would be reduced in the fentanyl condition. However, during exercise, plasma measures of NA spillover tended to be greater (P = 0.09) during fentanyl and CO and MAP are increased from rest, albeit to a smaller extent than in control conditions, suggesting that additional inputs on SNA need consideration. As suggested by the authors in the discussion of the present study, activation of the baroreflex may have occurred in the fentanyl condition leading to engagement of the SNA as a means to augment MAP. With fentanyl, baroreflex resetting may still occur through intact central command; however, the rise in MAP may be attenuated due to limited afferent feedback. Compared to the control condition, the lower MAP with fentanyl may lead to an ‘error signal’, the presence of which could engage the baroreflex and result in the activation of the SNA. Within the fentanyl condition, augmented SNA might be reflected in the somewhat greater levels of plasma NA and lower FVC. In short, baroreflex engagement in the fentanyl condition may have occurred to help increase MAP, thus masking the independent influence afferent signalling may have on elevating MAP. An alternative explanation for increased SNA could also be that the limited arterial inflow and oxygen delivery associated with fentanyl administration may have resulted in a greater degree of metabolite production. Augmented metabolite production for a given exercise intensity could create a greater stimulus for muscle afferents, allowing for enhanced signaling that could in part augment SNA if blockade was incomplete or overridden.

The present findings indicate that in a young, healthy population afferent feedback plays a key role in facilitating the pressor response to exercise, without which blood flow and oxygen delivery are reduced and leg oxygen consumption is impaired. As the exercise protocol in the present study was relatively short in duration, it is of interest to investigate what role afferent feedback may have in exercise tolerance and muscle fatigue during prolonged periods of exercise and what impact attenuated oxygen consumption could have in these conditions. On a related note, in contrast to young healthy adults, heart failure (Middlekauff & Sinoway, 2007) and heart transplant (Houssiere et al. 2007) populations exhibit an overactive pressor response to exercise and it has been suggested that the associated elevation in SNA may contribute to impaired exercise tolerance in this group (Houssiere et al. 2007). Potentially, the use of fentanyl to minimize the role of afferent feedback would provide valuable insight in these groups regarding the role augmented SNA may have on skeletal muscle blood flow during exercise.

The recent article by Amann et al. represents a key advance in our understanding of the role of afferent feedback and signalling in regulating the central and peripheral cardiovascular responses to exercise. The authors are commended for their use of a novel technique that seems to address many of the limitations of previous studies on this topic. In addition to their main findings of a role for afferent feedback in increasing MAP and subsequently muscle blood flow to the active muscle, a number of interesting observations were made that will stimulate future investigations on this topic. Given the role of afferent feedback, it will also likely encourage additional work regarding the specific factors responsible for activation and sensitization of group III and IV muscle afferents, how different disease states or conditions may modulate these factors, and how afferent feedback may be related to impaired exercise capacity in populations demonstrating exercise intolerance.

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