title: 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.
authors.affiliation: Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania audrey.stone@austin.utexas.edu.
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Stone
authors.affiliation: Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Copp
authors.affiliation: Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Kaufman
mesh_terms: D062565:Acid Sensing Ion Channels / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003064:Cnidarian Venoms / Q000494:pharmacology; D003655:Decerebrate State; D006614:Hindlimb / Q000098:blood supply; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects; D005082:Physical Exertion / Q000187:drug effects*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D058469:Receptors, Purinergic P2X / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C501880:APETx2 protein, Anthopleura elegantissima; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D003064:Cnidarian Venoms; C508711:L-161982; D058920:Purinergic P2X Receptor Antagonists; D058309:Receptors, Prostaglandin E, EP4 Subtype; D058469:Receptors, Purinergic P2X; D013876:Thiophenes; D014230:Triazoles; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate
keywords: chemoreflex; metaboreflex; muscle afferents