Muscle afferent ASIC3 upregulation mediates the exacerbated exercise pressor reflex in male rats following hindlimb ischemia-reperfusion.

We examined if the hindlimb muscle ischemia-reperfusion (IR) alters ASIC3-mediated muscle afferent activity in regulating the exercise pressor reflex (EPR). APETx2 (an ASIC3 antagonist) was arterially injected into the hindlimb before static muscle contraction. The mean arterial pressure (MAP) and heart rate (HR) were recorded. ASIC3-mediated MAP response was studied via intra-arterially injected lactic acid (LA). Western blot and immunofluorescence were used to determine the ASIC3 expression and location in L4-6 dorsal root ganglion (DRG). Calcium imaging was applied to detect pH6.7-induced Ca(2+) entry in the isolated muscle DRG neurons. IR amplified the peak MAP response to muscle contraction (sham vs. IR: p = 0.031), which was reduced by the blockage of ASIC3 with APETx2 (baseline vs. blockage: p < 0.001). The peak MAP responses to LA were increased in IR rats (sham vs. IR, 1 μmol/kg: p < 0.05; 2 and 4 μmol/kg: sham vs. IR, p < 0.01) and were reduced by APETx2 (baseline LA control vs. blockage: p = 0.013). ASIC3 protein expression was increased in IR L4-6 DRGs (sham vs. IR, p = 0.012). APETx2 attenuated the pH 6.7-induced Ca(2+) entry (ΔF340/F380: sham vs. IR, p = 0.017; IR vs. IR + APETx2, p = 0.003). Increased ASIC3 signaling amplifies muscle afferent activity and exacerbates the EPR following IR.