title: Vanilloid type 1 receptor and the acid-sensing ion channel mediate acid phosphate activation of muscle afferent nerves in rats.
abstract: Reflex cardiovascular responses to contracting skeletal muscle are mediated by mechanical and metabolic stimulation of thin-fiber muscle afferents. Diprotonated phosphate (H2PO4-) excites those thin-fiber nerves and evokes the muscle pressor reflex. The receptors mediating this response are unknown. Thus we examined the role played by purinergic receptors, vanilloid type 1 receptors (VR1), and acid-sensing ion channels (ASIC) in mediating H2PO4- -evoked pressor responses. Phosphate and blocking agents were injected into the arterial blood supply of the hindlimb muscles of 53 decerebrated rats. H2PO4- (86 mM, pH 6.0) increased mean arterial pressure by 25 +/- 2 mmHg, whereas monoprotonated phosphate (HPO4(2-), pH 7.5) had no effect. Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (a purinergic receptor antagonist, 2 mM) did not block the response. However, capsazepine (a VR1 antagonist, 1 mg/kg) attenuated the reflex by 60% and amiloride (an ASIC blocker, 6 microg/kg) by 52%. Of note, the H2PO4- -induced pressor response was attenuated by 87% when both capsazepine and amiloride were injected before the H2PO4-. In conclusion, VR1 and ASIC mediate the pressor response due to H2PO4-. The H2PO4- -evoked response was greater when VR1 and ASIC blockers were given simultaneously than when the respective blockers were given separately. Our laboratory's previous study has shown that H+ stimulates ASIC (but not VR1) on thin-fiber afferent nerves in evoking the reflex response. Thus VR1 and ASIC are likely to play a coordinated and interactive role in processing the muscle afferent response to H2PO4-. Furthermore, the physiological mechanisms mediating the response to H+ and H2PO4- are likely to be different.
authors.affiliation: Department of Medicine, Division of Cardiology, H047, Penn State College of Medicine, Milton S. Hershey Medical Center, 500 Univ. Dr., Hershey, PA 17033, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Gao
authors.forename: Oze
authors.initials: O
authors.lastname: Henig
authors.forename: Valerie
authors.initials: V
authors.lastname: Kehoe
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Sinoway
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
mesh_terms: D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003655:Decerebrate State; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000294:innervation; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D010756:Phosphoric Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects; D050916:TRPV Cation Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D062565:Acid Sensing Ion Channels; D004224:Diterpenes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010756:Phosphoric Acids; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D000584:Amiloride; C024353:resiniferatoxin; C071423:capsazepine; D002211:Capsaicin