Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

Abstract

Background/Aims: Limb ischemia occurs in peripheral artery disease (PAD). Sympathetic nerve activity (SNA) that regulates blood flow directed to the ischemic limb is exaggerated during exercise in this disease, and transient receptor potential channel A1 (TRPA1) in thin-fiber muscle afferents contributes to the amplified sympathetic response. The purpose of the present study was to determine the role of proteinase-activated receptor-2 (PAR2) in regulating abnormal TRPA1 function and the TRPA1-mediated sympathetic component of the exercise pressor reflex. Methods: A rat model of femoral artery ligation was employed to study PAD. Dorsal root ganglion (DRG) tissues were obtained to examine the protein levels of PAR2 using western blot analysis. Current responses induced by activation of TRPA1 in skeletal muscle DRG neurons were characterized using whole-cell patch clamp methods. The blood pressure response to static exercise (i.e., muscle contraction) and stimulation of TRPA1 was also examined after a blockade of PAR2. Results: The expression of PAR2 was amplified in DRG neurons of the occluded limb, and PAR2 activation with SL-NH2 (a PAR2 agonist) increased the amplitude of TRPA1 currents to a greater degree in DRG neurons of the occluded limb. Moreover, FSLLRY-NH2 (a PAR antagonist) injected into the arterial blood supply of the hindlimb muscles significantly attenuated the pressor response to muscle contraction and TRPA1 stimulation in rats with occluded limbs. Conclusions: The PAR2 signal in muscle sensory nerves contributes to the amplified exercise pressor reflex via TRPA1 mechanisms in rats with femoral artery ligation. These findings provide a pathophysiological basis for autonomic responses during exercise activity in PAD, which may potentially aid in the development of therapeutic approaches for improvement of blood flow in this disease.

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

“…It is well documented that the upregulation of P2 × 3 is known to contribute to purinergic pain-sensing system [65]. In a different neuropathological perspective, PAR2-related pain sensitivity maybe attributed to the upregulation or activation of TRPV1 [66,67] and TRPA1 [46,68,69] in DRG neurons.…”

Pulsatility Index as a Novel Parameter for Perfusion in Mouse Model of Hindlimb Ischemia

“…The assessment of blood flow recovery in small animals is critical for phenotyping genetic mouse models, evaluating the efficacy of novel vascular disease therapies, and investigating the safety of agents with potential toxic side effects [9,10]. Conventional noninvasive in vivo methods for assessing blood flow recovery are used for physiological investigations but are not reproducible, which prevents comparisons.…”