Evidence that A‐317567 is a selective ASIC antagonist for thin fiber muscle afferents in decerebrate cats

Abstract

Lactic acid is widely hypothesized to accumulate in contracting muscle to activate the thin fiber muscle afferents causing the exercise pressor reflex. Testing this hypothesis has been difficult because of the lack of a selective ASIC antagonist. We, therefore, examined if A-317567 attenuated the pressor and cardioaccelerator responses to popliteal arterial injections of lactic acid (0.2 to 0.5 ml, 24mM) and capsaicin (2–5 μg) as well as to tendon stretch. In decerebrate cats we found that A-317567 (10 mM; 0.5 ml) blocked the pressor-cardioaccelerator responses to lactic acid injection but had no effect on the pressor-cardioaccelerator responses to either capsaicin injection or tendon stretch. For example, the pressor response to lactic acid injection averaged 28 ± 8 mmHg before A-317567 and 4 ± 5 mmHg 10 minutes afterwards (p = 0.027; n = 4). In contrast, the pressor response to capsaicin injection averaged 33 ± 8 mm Hg before the ASIC antagonist and 33 ± 7 mm Hg afterwards (p = 0.78; n = 4). A dose of 0.5 ml of 1 mM A-317567 had no effect of the pressor and cardioaccelerator responses to arterial injections of lactic acid and capsaicin. Our data suggest that A-317567 is a specific blocker of ASIC channels and may be a useful tool to examine the role played by these channels in the exercise pressor reflex.