Muscarinic modulation of endogenous noradrenaline release from adrenergic terminals in the guinea-pig colon.
1 The present study examined the role of muscarinic receptors in the modulation of noradrenaline (NA) release in the guinea-pig isolated distal colon. The spontaneous endogenous NA overflow assayed by HPLC-ED was taken as an index of NA release from enteric noradrenergic nerve terminals. 2 Physostigmine (10 microM) significantly enhanced spontaneous endogenous NA overflow. Hyoscine (muscarinic antagonist), (R)-(-)-trihexyphenidyl and telenzepine (M1-selective antagonists), and 11[[2-[(diethylamino)methyl]-1-piperydil]acetyl]-5,11 -dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116, M2-selective antagonist) inhibited NA overflow in a concentration dependent manner, with the following EC50 values: 131.74 (18.19-953.96), 101.62 (58.83-175.60), 150 (60-330), 30 (5-170) nM, respectively. 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M1- and M3-selective antagonist) had no significant effect up to 100 microM. 3 The muscarinic agonist oxotremorine inhibited NA overflow in a concentration dependent manner, with an EC50 value of 0.67 (0.30-1.51) microM. The response to oxotremorine was inhibited by muscarinic antagonists with the following order of potency: hyoscine = (R)-(-)-trihexyphenidyl = telenzepine > 4-DAMP >> AF-DX 116. 4 In the presence of 3 microM tetrodotoxin (TTX), the effect of oxotremorine and 4-DAMP was unchanged, while hyoscine, (R)-(-)-trihexyphenidyl, telenzepine and AF-DX 116, instead of inhibiting, significantly enhanced NA overflow. 5 The present results indicate that, in the guinea-pig colon, endogenous acetylcholine sustains spontaneous NA release by activating muscarinic receptors possibly located on interneurones. In addition, inhibitory muscarinic receptors may exist on adrenergic terminals.
Marino
F
F
Department of Internal Medicine and Therapeutics, II Faculty of Medicine, University of Pavia, Italy.
Cosentino
M
M
De Ponti
F
F
Giaroni
C
C
Somaini
L
L
Bombelli
R
R
Ferrari
M
M
Aasen
A J
AJ
Lecchini
S
S
Frigo
G
G
D000109:Acetylcholine / Q000378:metabolism; D000320:Adrenergic Fibers / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000294:innervation / Q000378:metabolism*; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D013779:Tetrodotoxin; D010095:Oxotremorine; D000109:Acetylcholine; D009638:Norepinephrine