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

Audrey J. Stone, Steven W. Copp, Joyce S. Kim, Marc P Kaufman

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (227%, P < 0.019) and integrated (248%, 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.

Original languageEnglish (US)
Pages (from-to)1330-1336
Number of pages7
JournalJournal of Applied Physiology
Volume119
Issue number11
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Hindlimb
Reflex
Muscles
Dinoprostone
Lactic Acid
Acid Sensing Ion Channels
Adenosine Triphosphate
Injections

Keywords

  • Chemoreflex
  • Metaboreflex
  • Muscle afferents

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles. / Stone, Audrey J.; Copp, Steven W.; Kim, Joyce S.; Kaufman, Marc P.

In: Journal of Applied Physiology, Vol. 119, No. 11, 01.12.2015, p. 1330-1336.

Research output: Contribution to journalArticle

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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 (227{\%}, P < 0.019) and integrated (248{\%}, 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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