Activation of purinergic P2X receptors and transient receptor potential vanilloid type 1 (TRPV1) on muscle afferent nerve evokes the pressor response. Because P2X and TRPV1 receptors are sensitive to changes in pH, the aim of this study was to examine the effects of muscle acidification on those receptors-mediated cardiovascular responses. In decerebrated rats, the pH in the hindlimb muscle was adjusted by infusing acidic Ringer solutions into the femoral artery. Dialysate was then collected using microdialysis probes inserted into the muscles and pH was measured. The interstitial pH was 7.53±0.01, 7.22±0.02, 6.94±0.04, and 6.59±0.03 in response to arterial infusion of the Ringer solution at pH 7.4, 6.5, 5.5, and 4.5. Femoral arterial injection of , -methylene ATP (P2X receptor agonist) in the concentration of 0.25 mM (volume: 0.15 - 0.25 ml; and injection duration: 1 minute), at the infused pH of 7.4, 6.5 and 5.5, increased mean arterial pressure (MAP) by 29±2, 24±3, and 21±3 mmHg (P<0.05, pH 5.5 vs. pH 7.4). When pH levels in the infused solution were 7.4, 6.5, 5.5, and 4.5, capsaicin (1µg/kg), a TRPV1 agonist, was injected into the artery. This elevated MAP by 29±4, 33±2, 35±3, and 40±3 mmHg (P<0.05, pH 4.5 vs. pH 7.4). Furthermore, blocking acid sensing ion channel (ASIC) blunted pH effects on TRPV1 response. Our data indicate that 1) muscle acidosis attenuates P2X-mediated pressor response but enhances TRPV1 response; 2) exaggerated TRPV1 response may require lower pH in muscle and the effect is likely to be mediated via ASIC mechanisms.