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Research ArticleCARDIOVASCULAR

Presynaptic Muscarinic M2-Receptor-Mediated Inhibition of N-Type Ca2+ Channels in Cultured Sphenopalatine Ganglion: Direct Evidence for Acetylcholine Inhibition of Cerebral Nitrergic Neurogenic Vasodilation

J. Liu, M. S. Evans and T. J.-F. Lee
Journal of Pharmacology and Experimental Therapeutics July 2002, 302 (1) 397-405; DOI: https://doi.org/10.1124/jpet.302.1.397
J. Liu
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M. S. Evans
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T. J.-F. Lee
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This article has a correction. Please see:

  • Correction to “Presynaptic Muscarinic M2-Receptor-Mediated Inhibition of N-Type Ca2+Channels in Cultured Sphenopalatine Ganglion: Direct Evidence for Acetylcholine Inhibition of Cerebral Nitrergic Neurogenic Vasodilation” - September 01, 2002

Abstract

Results of previous pharmacological studies suggested that presynaptic muscarinic M2 receptors on cerebral perivascular nitric oxidergic (nitrergic) nerves mediated inhibition of nitric oxide release from these nerves. The inhibition was thought to be primarily attributable to a decreased Ca2+ influx through N-type Ca2+ channels on nitrergic nerves, but direct evidence supporting this hypothesis was not presented. In the present study, we used cultured rat sphenopalatine ganglion (SPG), a major source of nitrergic nerves to cerebral blood vessels, to investigate the role of muscarinic M2 receptors in modulating voltage-dependent Ca2+ channels. SPG neuronal soma and dendrites were immunoreactive for both N-type Ca2+ channels and muscarinic M2 receptors, indicating that muscarinic M2receptors were colocalized with N-type Ca2+ channels. Using the whole-cell voltage-clamp technique, we found that voltage-dependent Ca2+ currents in cultured SPG were largely blocked by ω-conotoxin, an N-type calcium channel antagonist, but were not affected by nifedipine, an L-type calcium antagonist. The Ca2+ current was inhibited by acetylcholine (ACh) and arecaidine but-2-ynyl ester tosylate (ABET), a preferential muscarinic M2-receptor agonist, in a concentration-dependent manner. The inhibition was reversed by atropine and methoctramine (a muscarinic M2-receptor antagonist), but was not affected by muscarinic M1-, M3-, or M4-receptor antagonists. Consistent with this, preferential muscarinic M1-receptor agonists McN-A-343 and oxotremorine did not affect the Ca2+ current. Furthermore, pretreatment with pertussis toxin and guanosine 5′-O-(3-thio)triphosphate prevented ACh and ABET inhibition of Ca2+ currents. These results are consistent with pharmacological findings in the pig basilar arteries and provide direct evidence supporting our hypothesis that M2-receptor-mediated inhibition of cerebral nitrergic neurogenic vasodilation is due to a Gi-protein-mediated suppression of Ca2+ influx via voltage-dependent N-type Ca2+ channels on perivascular nerves.

Footnotes

  • This work was supported by National Institutes of Health Grants HL 27763 and HL 47574, AHA/IHA (9807871), and SIU-CRC/EAM (to T.J.-F.L.) and R29NS34564 (to M.S.E.).

  • Abbreviations:
    ACh
    acetylcholine
    SPG
    sphenopalatine ganglion
    l-NNA
    nitro-l-arginine
    ttx
    tetrodotoxin
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    ABET
    arecaidine but-2-ynyl ester tosylate
    4-DAMP
    4-diphenylacetoxy-N-methylpiperidine
    CTX
    ω-conotoxin
    8-bromo-cAMP
    8-bromoadenosine 3′,5′-cyclic monophosphate
    NO
    nitric oxide
    NOS
    nitric-oxide synthase
    PBS
    phosphate-buffered saline
    MOPS
    3-[N-morpholino]propane-sulfonic acid
    PTX
    pertussis toxin
    U-46619
    9,11-dideoxy-9α,11α-epoxymethanoprostaglandin F2α
    MR16728
    (N-(N′-hexamethylene-imino)-propyl-phenyl-cyclohexyl-methyl acetamide
    TNS
    transmural nerve stimulation
    • Received February 12, 2002.
    • Accepted March 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 1
1 Jul 2002
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Research ArticleCARDIOVASCULAR

Presynaptic Muscarinic M2-Receptor-Mediated Inhibition of N-Type Ca2+ Channels in Cultured Sphenopalatine Ganglion: Direct Evidence for Acetylcholine Inhibition of Cerebral Nitrergic Neurogenic Vasodilation

J. Liu, M. S. Evans and T. J.-F. Lee
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 397-405; DOI: https://doi.org/10.1124/jpet.302.1.397

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Research ArticleCARDIOVASCULAR

Presynaptic Muscarinic M2-Receptor-Mediated Inhibition of N-Type Ca2+ Channels in Cultured Sphenopalatine Ganglion: Direct Evidence for Acetylcholine Inhibition of Cerebral Nitrergic Neurogenic Vasodilation

J. Liu, M. S. Evans and T. J.-F. Lee
Journal of Pharmacology and Experimental Therapeutics July 1, 2002, 302 (1) 397-405; DOI: https://doi.org/10.1124/jpet.302.1.397
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