Background: Femoral artery occlusion in rats has been used to study human peripheral artery disease (PAD) (1-5). The responses of arterial blood pressure (BP) and sympathetic nerve activity are exaggerated during static exercise in PAD rats with femoral artery occlusion (3-5). Aims: The purpose of the current study was to examine if heat treatment (a prior heat exposure) has beneficial effects on the exaggerated exercise pressor reflex in PAD rats. We further determined if temperature sensitive P2X receptor was engaged in the effects of heat treatment. Methods: The pressor response to static muscle contraction was recorded to determine the exercise pressor reflex. Also, αβ-methylene ATP was injected into the arterial blood supply of the hindlimb muscles to stimulate P2X receptors in the muscle afferent nerves. Results: Basal muscle temperature (Tm) was 35.6±0.1 °C in control rats (n=3); and 34.2±0.1 °C in PAD rats (n=5; P<0.05 vs. control rats). As Tm was increased by ~1.5 °C and this was maintained for 30 min, core temperature was not altered in control group and PAD group. The heat treatment was performed 2 times daily for 3 days. Then we examined the BP response to static muscle contraction. The greater mean arterial pressure (MAP) response was observed in PAD rats (31±5 mmHg in PAD rats/n=6 vs. 22±3 mmHg in control rats/n=8; P<0.05). Heat treatment attenuated amplification of BP response in PAD rats (MAP response: 24±3 mmHg in PAD rats with heat treatment/n=5; P<0.05 vs. no heat treatment). Note that no significant difference in developed muscle tension during muscle contraction was seen in control rats and PAD rats with heat treatment or without heat treatment (P>0.05). In addition, heat treatment attenuated enhancement in MAP response induced by αβ-methylene ATP injected into the arterial blood supply of the hindlimb muscles of PAD rats (20±4 mmHg in control rats/n=5; 41±4 mmHg in PAD rats/n=6 and 26±5 mmHg in PAD rats with heat treatment; P<0.05, PAD vs. control and PAD with heat treatment). Conclusion: A prior heat exposure plays an inhibitory role in modifying exaggeration of the exercise pressor reflex in PAD and P2X is likely a part of mechanisms engaged in the heat treatment.