Authors: Marino, F.¹; Cosentino, M.¹; De Ponti, F.¹; Giaroni, C.¹; Somaini, L.¹; Bombelli, R.¹; Ferrari, M.¹; Aasen, A.J.²; Lecchini, S.¹; Frigo, G.¹

Source: Journal of Autonomic Pharmacology, Volume 17, Number 6, December 1997 , pp. 365-372(8)

Publisher: Wiley-Blackwell

Abstract:

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 μm) 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 μm.

3 The muscarinic agonist oxotremorine inhibited NA overflow in a concentration dependent manner, with an EC₅₀ value of 0.67 (0.30-1.51) μm. 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 μmtetrodotoxin (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.

Document Type: Original article

DOI: http://dx.doi.org/10.1046/j.1365-2680.1997.00057.x

Affiliations: 1: Department of Internal Medicine and Therapeutics, II Faculty of Medicine, University of Pavia, Via Ottorino Rossi n. 9, 21100 Varese VA, Italy, 2: Department of Pharmacy, University of Oslo, N-0317 Oslo 3, Norway

Publication date: 1997-12-01

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