Muscarinic modulation of endogenous noradrenaline release from adrenergic terminals in the guinea-pig colon

F. Marino, M. Cosentino, F. De Ponti, C. Giaroni, L. Somaini, R. Bombelli, M. Ferrari, A.J. Aasen, S. Lecchini, G. Frigo
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引用次数: 6

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 μm 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.

毒蕈碱调节豚鼠结肠肾上腺素能末端内源性去甲肾上腺素释放
本研究探讨了毒蕈碱受体在豚鼠离体远端结肠中调节去甲肾上腺素(NA)释放中的作用。以HPLC-ED法测定自发性内源性NA溢出量作为NA从肠内去甲肾上腺素能神经末梢释放的指标。10 μm的毒豆碱显著增强自发性内源性NA溢出。水莨菪碱(muscarinic拮抗剂)、(R)-(-)-三己苯基和telenzepine (m1选择性拮抗剂)和11[[2-[(二乙基氨基)甲基]-1-胡椒吡啶]乙酰基]-5,11-二氢- 6h -pyrido[2,3-b][1,4]苯二氮平-6-one (afdx 116, m2选择性拮抗剂)抑制NA溢出呈浓度依赖性,EC50值分别为131.74(18.19-953.96)、101.62(58.83-175.60)、150(60-330)、30 (5-170)nm。4-二苯基乙酰氧基- n -甲基哌啶甲氧基(4-DAMP, M1-和M3-选择性拮抗剂)在100 μm范围内无显著作用。毒蕈碱激动剂oxotremorine以浓度依赖性的方式抑制NA溢出,EC50值为0.67 (0.30-1.51)μm。毒蕈碱拮抗剂的效价顺序为:海莨菪碱= (R)-(-)-三己苯基= telenzepine >4-DAMP祝辞祝辞AF-DX 116。4 .在3 μm河蟹毒素(TTX)存在下,氧tremorine和4- damp的作用不变,而海莨菪碱、(R)-(-)- trihexphenidyl、telenzepine和AF-DX 116不仅没有抑制NA溢出,反而显著增强NA溢出。目前的结果表明,在豚鼠结肠中,内源性乙酰胆碱通过激活可能位于中间神经元上的毒蕈碱受体来维持NA的自发释放。此外,抑制性毒蕈碱受体可能存在于肾上腺素能末端。
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