Muscle Afferent Receptors Engaged in Augmented Sympathetic Responsiveness in Peripheral Artery Disease

Jianhua Li,Jihong Xing

doi:10.3389/fphys.2012.00247

Abstract

The exercise pressor reflex (EPR) is a neural control mechanism responsible for the cardiovascular responses to exercise. As exercise is initiated, thin fiber muscle afferent nerves are activated by mechanical and metabolic stimuli arising in the contracting muscles. This leads to reflex increases in arterial blood pressure (BP) and heart rate primarily through activation of sympathetic nerve activity (SNA). Studies of humans and animals have indicated that the EPR is exaggerated in a number of cardiovascular diseases. For the last several years, studies have specifically employed a rodent model to examine the mechanisms at receptor and cellular levels by which responses of SNA and BP to static exercise are heightened in peripheral artery disease (PAD), one of the most common cardiovascular disorders. A rat model of this disease has well been established. Specifically, femoral artery occlusion is used to study intermittent claudication that is observed in human PAD. The receptors on thin fiber muscle afferents that are engaged in this disease include transient receptor potential vanilloid type 1 (TRPV1), purinergic P2X, and acid sensing ion channel (ASIC). The role played by nerve growth factor in regulating those sensory receptors in the processing of amplified EPR was also investigated. The purpose of this review is to focus on a theme namely that PAD accentuates autonomic reflex responses to exercise and further address regulatory mechanisms leading to abnormal sympathetic responsiveness. This review will present some of recent results in regard with several receptors in muscle sensory neurons in contribution to augmented autonomic reflex responses in PAD. Review of the findings from recent studies would lead to a better understanding in integrated processing of sympathetic nervous system in PAD.

Highlights

During exercise, sympathetic nervous activity (SNA) increases and this leads to rises in blood pressure (BP) and heart rate (HR), myocardial contractility, and peripheral vasoconstriction (Victor et al, 1988; Sinoway et al, 1989)
Given that administration of nerve growth factor (NGF)-Ab into the hindlimb muscles significantly attenuates occlusion-enhanced protein levels of ASIC3 in dorsal root ganglion (DRG) tissues, these results suggest that NGF that is increased in sensory nerves of occluded limbs contributes to augmented reflex SNA and BP responses to stimulation of chemically, but not mechanically sensitive muscle afferent nerves
Findings of the completed studies suggest that enhanced protein levels of TRPV1, P2X3, and ASIC3 in muscle afferent nerves and amplified responses of those receptors contributes to the exaggerated reflex sympathetic and pressor responses to their individual receptor stimulus (Figure 5)

Summary

Introduction

Sympathetic nervous activity (SNA) increases and this leads to rises in blood pressure (BP) and heart rate (HR), myocardial contractility, and peripheral vasoconstriction (Victor et al, 1988; Sinoway et al, 1989). A basic mechanism termed the “Exercise Pressor Reflex” (EPR; Coote et al, 1971; McCloskey and Mitchell, 1972; Mitchell et al, 1977, 1983) is thought to contribute to sympathetic engagement during exercise (Figure 1) This autonomic reflex is initiated as thin fiber afferents arising from contracting skeletal muscle are engaged (McCloskey and Mitchell, 1972; Mitchell et al, 1983; Kaufman and Forster, 1996a). Group III afferents are predominantly mechanically sensitive (mechanoreceptor) and Group IV afferents are predominantly metabosensitive (metaboreceptor; Kaufman et al, 1984) When these receptors are stimulated, thin fiber muscle afferent nerves are engaged, cardiovascular nuclei in the brainstem are activated, SNA increases, and BP and HR rise (Mitchell et al, 1983). The sympathetic and cardiovascular responses to exercise are modulated by the “Central Command” (Goodwin et al, 1972; Waldrop et al, 1996), and the arterial baroreflex (Potts and Li, 1998; Fadel et al, 2001)

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