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 m odulation of noradrenaline (NA) release in the guinea-pig isolated dis tal colon. The spontaneous endogenous NA overflow assayed by HPLC-ED w as taken as an index of NA release from enteric noradrenergic nerve te rminals. 2 Physostigmine (10 mu M) significantly enhanced spontaneous endogenous NA overflow. Hyoscine (muscarinic antagonist), (R)-(-)-trih exyphenidyl and telenzepine (M-1-selective antagonists), and etyl]-5,1 1-dihydro-6H-pyrido[2,3-b][1,4]benzodiaze pine-6-one (AF-DX 116, M-2-s elective antagonist) inhibited NA overflow in a concentration dependen t manner, with the following EC50 values: 131.74 (18.19-953.96), 101.6 2 (58.83-175.60), 150 (60-330), 30 (5-170) nh, respectively. 4-dipheny lacetoxy-N-methylpiperidine methiodide (4-DAMP, M-1- and M-3- selectiv e antagonist) had no significant effect up to 100 mu M. 3 The muscarin ic agonist oxotremorine inhibited NA overflow in a concentration depen dent manner, with an EC50 value of 0.67 (0.30-1.51) mu M. The response to oxotremorine was inhibited by muscarinic antagonists with the foll owing order of potency: hyoscine = (R)-(-)-trihexyphenidyl = telenzepi ne > 4-DAMP >> AF-DX 116. 4 In the presence of 3 mu M tetrodotoxin (TT X), the effect of oxotremorine and 4-DAMP was unchanged, while hyoscin e, (R)-(-)-trihexyphenidyl, telenzepine and AF-DX 116, instead of inhi biting, significantly enhanced NA overflow. 5 The present results indi cate that, in the guinea-pig colon, endogenous acetylcholine sustains spontaneous NA release by activating muscarinic receptors possibly loc ated on interneurones. In addition, inhibitory muscarinic receptors ma y exist on adrenergic terminals.