The exercise pressor reflex arises from contracting skeletal muscle and is believed to play a role in evoking the cardiovascular responses to static exercise, effects which include increases in arterial pressure and heart rate. In part, this reflex is believed to be evoked by metabolic and mechanical stimulation of thin fiber muscle afferents. Lactic acid is known to be an important metabolic stimulus evoking the reflex. Until recently, the only antagonist for acid sensitive ion channels (ASICs), the receptors to lactic acid, was amiloride, a substance which is also a potent antagonist for both epithelial sodium channels (ENaCs) as well as voltage gated sodium channels. Recently, a second compound, A-317567, has been shown to be an effective and selective antagonist to ASICs in vitro. Consequently, we measured the pressor responses to static contraction of the triceps surae muscles in decerebrate cats before and after popliteal arterial injection of A-317567. We found that this ASIC antagonist significantly attenuated by half (P < 0.05) the pressor responses to both contraction and to lactic acid injection into the popliteal artery. In contrast, A-3175657 had no effect on the pressor responses to tendon stretch, a pure mechanical stimulus, and to popliteal arterial injection of capsaicin, which stimulated TRPV1 channels. We conclude that ASICs on thin fiber muscle afferents play a substantial role in evoking the metabolic component of the exercise pressor reflex.