Cardiovascular regulation by skeletal muscle reflexes in health and disease

Abstract

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.

Fig. 1.

The exercise pressor reflex arc. Skeletal muscle contraction excites group III and group IV sensory afferent neurons through several putative stimuli. Stretch or the application of pressure to skeletal muscle distorts the receptive field of mechanically sensitive receptors located predominately on group III afferent neurons. These mechanoreceptors have yet to be identified but are likely mechanogated cation, potassium, or calcium channels. Metabolites released during muscle contraction such as potassium, lactic acid, bradykinin, analogs of ATP, by-products of arachidonic acid metabolism, and diprotonated phosphate excite metabolically sensitive receptors located predominately on group IV afferent neurons. Pharmacological agonists for acid-sensing ion channels (ASICs), bradykinin receptors, transient potential vanilloid receptor 1 (TRPV1), purinergic receptors, and cannabanoid receptors have been demonstrated to evoke group IV afferent activity. However, there are likely other potential metaboreceptors that have yet to be identified. Group III and group IV afferent sensory neurons transmit impulses, via the spinal cord, to the cardiovascular control centers located within the medullary region of the brain stem, specifically the nucleus tractus solitarius, rostral ventrolateral medulla, and caudal ventrolateral medulla, as well as other secondary nuclei. Central processing of this input promotes increases in sympathetic nerve activity and withdrawal of parasympathetic nerve activity. Thus heart rate, arterial blood pressure, and vascular resistance are reflexively increased upon the onset of muscle contraction.

Fig. 2.

Cumulative histogram of group IV afferent impulses (Imp) before, during, and after electrically induced static contraction. A: in 8 group IV sensory neurons, afferent activity was elevated during static contraction (denoted by black bar) compared with the impulses recorded 1 min before and 2 min after contraction. B: administration of indomethacin (5 mg/kg iv) markedly reduced the discharge of the same group IV afferent neurons during static contraction. Indomethacin did not affect the discharge of afferents before or following contraction. Data adapted from Rotto et al. (135).

Fig. 3.

Cumulative histogram of group III afferent impulses before, during, and after electrically induced static contraction. A: in 11 group III sensory neurons, afferent activity was elevated during static contraction (denoted by black bar, Cx). B: the discharge of group III afferents was markedly reduced during contraction 60 min after the injection of gadolinium trichloride (10 mM in 1 ml) into the femoral artery. C: group III afferent impulses during contraction were partially restored after 120 min. Data adapted from Hayes and Kaufman (41).

Fig. 4.

A representative tracing of the cardiovascular response to electrically induced static contraction in normotensive and hypertensive rats. The pressor and sympathetic response to a given amount of tension generated during electrically induced static contraction is greater in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. ABP, arterial blood pressure; RSNA, renal sympathetic nerve activity. Tracing adapted from Mizuno et al. (119).

Fig. 5.

Stimulation of the metaboreflex and the mechanoreflex evokes an exaggerated pressor response in hypertension. A: injection of graded doses of capsaicin into the femoral artery of hypertensive rats produced an exaggerated increase in mean arterial pressure (MAP) compared with normotensive rats. Sal, saline; Veh, vehicle. B: passive stretch of the hindlimb evoked a significantly greater pressor response in SHRs compared with WKY rats, specifically from 34 to 100% maximal tension development. *SHRs significantly different from WKY. †Significantly different from the preceding stimulus. Significance was set at P < 0.05. Data adapted from Leal et al. (86).

Fig. 6.

Electrically induced static contraction evokes an exaggerated sympathetic response in rats with dilated cardiomyopathy. Static contraction of the hindlimb for 30 s (A) evoked a significantly (*P < 0.05) greater change in RSNA and lumbar SNA (LSNA) in rats with ischemia-induced dilated cardiomyopathy (black bars) compared with normal control rats (white bars) (B). Change in RSNA (C) and LSNA (D) was significantly greater for a given amount of tension generated over the 30-s contraction [tension time index (TTI)]. Int, integrated; AU, arbitrary units. Data adapted from Koba et al. (79).