Lactic Acid, Acid-Sensing Ion Channels and the Exercise Pressor Reflex

Abstract

Lactic acid is one of the products of contraction that is thought to be a metabolic stimulus that evokes reflex increases in arterial pressure, heart rate and ventilation, otherwise known as the exercise pressor reflex. For example, injection of lactic acid into the arterial supply of skeletal muscle has been shown to evoke reflex increases in arterial pressure, heart rate and ventilation that approximate those occurring during static exercise; whereas neutral controls failed to evoke any reflex cardiovascular effects. Moreover, injection of lactic acid into the arterial supply of skeletal muscle has been shown to increase the discharge of the group III and IV muscle afferents that comprise the afferent arm of this reflex. To demonstrate lactic acid contributes to the elicitation of the exercise pressor reflex, we needed to show that blockade of a specific receptor to the metabolite prevents or attenuates the expression of the reflex. This demonstration has been difficult to achieve for lactic acid because its receptor on group III and IV afferents was not clearly identified. Lactic acid is thought to activate both the TRPV 1 receptor as well as the acid sensing ion channel (ASIC). Recently, the TRPV 1 receptor was shown to play little if any role in evoking the metabolic component of the exercise pressor reflex. Although this finding pointed towards the ASIC receptor, the list of tested selective antagonists is small. One candidate is amiloride, which has been shown to block ASICs in vitro. Unfortunately, amiloride has also been shown to antagonize voltage-gated sodium channels (ENaC), suggesting it may not be an ideal antagonist to investigate the role of lactic acid in vivo. Another candidate is A-317567, a compound shown in vitro to be selective for ASICs in general. A-317567 does not appear in block ENaC at doses that effective antagonize ASICs but the in vitro kinetics are somewhat complex. In the experiments to be reported, we have used amiloride and A-317567 to determine whether lactic acid plays a role in the exercise pressor reflex. Finding a suitable selective antagonist for ASIC would enable us to examine the role played by this channel and by lactic acid in the generation of the metabolic component of the exercise pressor reflex.