ASIC₃ contributes to the blunted muscle metaboreflex in heart failure

INTRODUCTION: During exercise, the sympathetic nervous system is activated and blood pressure and HR increase. In heart failure (HF), the muscle metaboreceptor contribution to sympathetic outflow is attenuated and the mechanoreceptor contribution is accentuated. Previous studies suggest that lactic acid stimulates acid-sensing channel subtype 3 (ASIC₃), inducing a neurally mediated pressor response. Thus, we hypothesized that the pressor response to ASIC₃ stimulation is smaller in HF rats because of attenuation in expression and function of ASIC₃ in sensory nerves. METHODS: Lactic acid was injected into the arterial blood supply of the hind limb to stimulate ASIC₃ in muscle afferent nerves and evoke muscle metaboreceptor response in control rats and HF rats. In addition, western blot analysis was used to examine expression of ASIC₃ in dorsal root ganglion (DRG) and patch clamp to examine current response with ASIC₃ activation. RESULTS: Lactic acid (4 μmol·kg) increased mean arterial pressure by 28 ± 5 mm Hg in controls (n = 6) but only by 16 ± 3 mm Hg (P < 0.05 vs control) in HF (n = 8). In addition, HF decreased the protein levels of ASIC₃ in DRG (optical density, 1.03 ± 0.02 in control, vs 0.79 ± 0.03 in HF; P < 0.05; n = 6 in each group). The peak current amplitude of dorsal DRG neuron in response to ASIC₃ stimulation is smaller in HF rats than that in control rats. CONCLUSIONS: Compared with those in controls, cardiovascular responses to lactic acid administered into the hind limb muscles are blunted in HF rats owing to attenuated ASIC₃. This suggests that ASIC₃ plays a role in engagement in the attenuated metaboreceptor component of the exercise pressor reflex in HF.