Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles

Abstract

In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P < 0.019) and integrated (↓48%, P < 0.004) pressor components of the reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs.

Inorganic phosphate and lactate potentiate the pressor response to acidic stimuli in rats

“…Therefore, early during exercise, when inorganic phosphate and lactate concentrations increase greatly but the change in pH is limited (Broxterman et al., 2017; Karlsson & Saltin, 1970), other mechanisms or metabolites need to compensate for the lack of effectiveness of inorganic phosphate and lactate to produce a pressor response. This indirectly supports recent results from our laboratory showing that the mechanisms responsible for evoking the exercise pressor reflex are redundant and arise from a wide variety of receptors (Stone, Copp, Kim, & Kaufman, 2015). Among the different mechanisms possible, the activation of P2X receptors owing to ATP release early during exercise appears to be a good candidate (Hanna & Kaufman, 2004; Hayes, McCord, & Kaufman, 2008).…”

Antihypertensive Treatment Fails to Control Blood Pressure During Exercise

“…Potential targets could include chemically sensitive afferents and associated receptors in skeletal muscle. Since there are many receptors involved in the metaboreflex and much redundancy exists in humans 36 ,blocking one receptor may not effectively reduce the exercise pressor response5,20,36 .…”

TRPV1 and BDKRB2 receptor polymorphisms can influence the exercise pressor reflex

“…Although the modest effects of individual genetic variants on BP and heart rate during exercise are not surprising given the likely redundancy of the muscle metaboreflex and the integrative complexity of BP regulation during exercise (Stone et al . ), we observed additive effects of TRPV1 rs222747 and BDKRB2 rs1799722 resulting in ∼22–23% differences in systolic and diastolic BP responses between individuals carrying both minor alleles compared to individuals carrying no minor alleles. Subgroup analysis determined that these differences were observed primarily in men, and corresponded similarly to reported differences between BP responses during static handgrip exercise in normotensive and hypertensive populations (Delaney et al .…”

“…; Stone et al . ), have sought to identify the roles of specific metabolites responsible for engaging the exercise pressor reflex, focusing specifically on stimuli to TRPV1, BDKRB2, ASIC, P2RX4 and PTGER2 receptor pathways (Greaney et al . ).…”