title: Protons modulate perivascular axo-axonal neurotransmission in the rat mesenteric artery.
abstract: OBJECTIVE
  Previous studies have demonstrated that nicotine releases protons from adrenergic nerves via stimulation of nicotinic ACh receptors and activates transient receptor potential vanilloid-1 (TRPV1) receptors located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves, resulting in vasodilatation. The present study investigated whether perivascular nerves release protons, which modulate axon-axonal neurotransmission.
  
  
  METHODS
  Perfusion pressure and pH levels of perfusate in rat-perfused mesenteric vascular beds without endothelium were measured with a pressure transducer and a pH meter respectively.
  
  
  RESULTS
  Periarterial nerve stimulation (PNS) initially induced vasoconstriction, which was followed by long-lasting vasodilatation and decreased pH levels in the perfusate. Cold-storage denervation of the preparation abolished the decreased pH and vascular responses to PNS. The adrenergic neuron blocker guanethidine inhibited PNS-induced vasoconstriction and effects on pH, but not PNS-induced vasodilatation. Capsaicin (CGRP depletor), capsazepine and ruthenium red (TRPV1 inhibitors) attenuated the PNS-induced decrease in pH and vasodilatation. In denuded preparations, ACh caused long-lasting vasodilatation and lowered pH; these effects were inhibited by capsaicin pretreatment and atropine, but not by guanethidine or mecamylamine. Capsaicin injection induced vasodilatation and a reduction in pH, which were abolished by ruthenium red. The use of a fluorescent pH indicator demonstrated that application of nicotine, ACh and capsaicin outside small mesenteric arteries reduced perivascular pH levels and these effects were abolished in a Ca(2+) -free medium.
  
  
  CONCLUSIONS
  These results suggest that protons are released from perivascular adrenergic and CGRPergic nerves upon PNS and these protons modulate transmission in CGRPergic nerves.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime, Japan; Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Takatori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hirai
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Ozaki
authors.forename: Panot
authors.initials: P
authors.lastname: Tangsucharit
authors.forename: Satoko
authors.initials: S
authors.lastname: Fukushima-Miyashita
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Goda
authors.forename: Narumi
authors.initials: N
authors.lastname: Hashikawa-Hobara
authors.forename: Nobufumi
authors.initials: N
authors.lastname: Ono
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kawasaki
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D006145:Guanethidine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008464:Mecamylamine / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000294:innervation*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011522:Protons; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018679:Cholinergic Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011522:Protons; D013565:Sympatholytics; D012430:Ruthenium Red; D008464:Mecamylamine; D001285:Atropine; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D000109:Acetylcholine; D002211:Capsaicin; D006145:Guanethidine