Skeletal muscle contraction triggers rapid onset pressor responses in cardiovascular disease

Peripheral artery disease (PAD), which affects ∼10 million Americans (Hirsch et al. 2006), is an atherosclerotic process resulting in narrowing of the arteries perfusing the legs, subsequently reducing limb blood flow. The pathophysiology of PAD is characterized by intermittent claudication, attributed to inadequate blood flow to the legs to meet the metabolic demands of the working muscles (Hirsch et al. 2006). In spite of exercise-induced leg pain, regular exercise is routinely recommended for patients with PAD, and recent trials document the beneficial effects of chronic exercise training to increase claudication onset time and maximal walking distance (Gardner et al. 2012). The neurocirculatory responses to acute exercise are partially mediated by the exercise pressor reflex, a feedback neural mechanism originating in the working muscle. Activation of the sensory component of the exercise pressor reflex, comprising both mechanically (i.e. muscle mechanoreflex) and chemically (i.e. muscle metaboreflex) sensitive afferent fibres, contributes to neurocirculatory modulation during exercise (Kaufman et al. 1983). An experimental rat model of PAD has been developed, in which ligation of the femoral artery reduces hindlimb blood flow such that blood flow is adequate at rest but is compromised during muscle contraction, simulating the blood flow patterns observed in human manifestations of the disease (Tsuchimochi et al. 2010). In this model, static contraction of the hindlimb muscle whose femoral artery had been occluded evoked greater cardiovascular responses than static contraction of the contralateral freely perfused hindlimb muscle (Tsuchimochi et al. 2010), suggesting that the exercise pressor reflex is augmented in rats whose femoral arteries were ligated. While these findings in experimental animal models increase our understanding of abnormal neural cardiovascular control during exercise in PAD, it is important that these findings be translated to the human condition. In this issue of The Journal of Physiology, Muller and colleagues publish a study examining the acute cardiovascular responses to plantar flexion exercise in humans with PAD and demonstrate exaggerated increases in blood pressure during exercise in both the most and least affected limb of PAD subjects (Muller et al. 2012). The study also utilized involuntary electrically evoked plantar flexion and similarly found a greater blood pressure response in PAD patients. The authors interpret these exaggerated pressor responses to both voluntary and involuntary exercise as being primarily mediated by the mechanical component of the exercise pressor reflex and further suggest that chronic limb ischaemia may sensitize the sensory afferent fibres involved in this response. To begin to address the mechanisms underlying the exaggerated pressor responses to muscle contraction in PAD, the authors infused the non-specific antioxidant ascorbate prior to exercise. After intravenous administration of ascorbate, the augmented blood pressure responses to exercise in PAD patients were attenuated (Muller et al. 2012), suggesting a role for oxidative stress in contributing to the abnormal pressor responses to low-intensity exercise (Muller et al. 2012). Interestingly, reactive oxygen species do not appear to be responsible for the augmented pressor responses to both static contraction and tendon stretch in rodent models of PAD (McCord et al. 2011). Therefore, further study is warranted to reconcile these apparent differences. In healthy adults, low-intensity skeletal muscle contraction – both voluntary and involuntary – is thought to preferentially activate the muscle mechanoreflex (primarily group III sensory fibres), similar to passive tendon stretch used in animal models (Herr et al. 1999; Tsuchimochi et al. 2010). However, the blood flow impairments in PAD, which are graded with respect to disease severity, may not only sensitize the sensory fibres, but may also stimulate the muscle metaboreflex (primarily group IV sensory fibres). This unique characteristic of PAD, coupled with the known polymodal nature of the afferent sensory fibres that contribute to the exercise pressor reflex (Kaufman et al. 1983), makes the distinction between these two reflex mechanisms difficult. Regardless of the relative contribution of the mechanoreflex and metaboreflex to cardiovascular control during exercise, an exaggerated skeletal muscle reflex contributes to the aberrant pressor responses in PAD, which is clearly demonstrated by Muller and colleagues. The model of exercise used in this study is important because low-intensity dynamic exercise generally elicits minimal pressor responses at exercise onset in healthy adults. However, in PAD patients in the current study, blood pressure increased within the first 20 s, and remained augmented compared to healthy adults for the duration of exercise. While examining the cardiovascular responses during steady-state exercise is a bedrock principle in exercise physiology, data such as these highlight abnormalities at exercise onset. The rapid onset pressor response to low-level exercise is highly relevant when considering that many activities of daily living are not necessarily steady-state, but rather short-lived and submaximal. Episodic surges in blood pressure throughout a normal day may increase both short- and long-term cardiovascular disease risk. In addition, heightened sympathoexcitation is likely to contribute to the exaggerated pressor responses observed during exercise in patients with PAD. Interestingly, abnormal sympathoexcitatory and pressor responses to low-intensity dynamic handgrip exercise were recently reported in hypertensive humans (Vongpatanasin et al. 2011). Thus, rapid onset pressor and sympathoexcitatory responses to skeletal muscle contraction may be characteristic of multiple cardiovascular diseases, perhaps indicating that more consideration should be given to the time course at which blood pressure increases during exercise, as opposed to only focusing on the steady-state, or maximal, values of blood pressure that are achieved. Although the prognostic significance of abnormal pressor responses at the onset of low-intensity exercise is not yet known, this line of research nevertheless merits further study.