What is the clinical evidence from this study?

Study design: Other. Population: Exercise pressor reflex (n=29). Intervention: Combined blockade of ASIC3, P2X, and EP4 receptors (APETx2, PPADS, L161982) vs. Baseline (before drug) and individual blockade. Primary outcome: Peak pressor response to static contraction (p=0.019).

October 16, 2015Journal of Applied Physiology40 citationsOpen Access

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

ASAudrey J. Stone SCSteven W. Copp JKJoyce Kim

Key Result

Combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors attenuated the peak pressor component of the exercise pressor reflex by 27% in rats with freely perfused hindlimbs.

Structured PICO

Does combined blockade of ASIC3, P2X, and EP4 receptors attenuate the exercise pressor reflex in rats with freely perfused hindlimb muscles?

Population

Adult male Sprague-Dawley rats (n=29, weighing 415 ± 11 g), decerebrated, unanesthetized, with freely perfused hindlimb muscles.

Intervention

Combined blockade of P2X receptors (PPADS 10 mg/kg), ASIC3 channels (APETx2 100 μg/kg), and EP4 receptors (L161982 2 μg/kg) injected into the arterial supply of the hindlimb.

Comparator

Individual blockade of the same receptors (PPADS alone, APETx2 alone, L161982 alone) and intravenous injection of combined blockade.

Outcome

Peak and integrated pressor components of the exercise pressor reflex (changes in mean arterial pressure) during 30 seconds of static contraction of the hindlimb muscles.surrogate

Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs, suggesting redundant mechanisms control the cardiovascular system during exercise.

Main Result

p-value: p=0.019

Limitations

The contraction period of 30 s was too short to allow for enough interstitial fluid to be collected to measure metabolite concentrations.
Species differences between rats and cats regarding receptor numbers and metabolite production may complicate interpretation.
The 30-s contraction period was too short to allow for enough interstitial fluid to be collected to measure interstitial concentrations of metabolites.

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.

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