Blanquet F, Abysique A, Gonella J
Faculté des Sciences et Techniques de St Jérôme, Départment de Physiologie et Neurophysiologie, Marseille, France.
J Auton Nerv Syst. 1994 Mar;46(3):217-27. doi: 10.1016/0165-1838(94)90039-6.
The aim of the present study was to elucidate the role of the non-M1 muscarinic receptors, in the extrinsic and intrinsic nerve control of in vivo colonic motility. Experiments were performed on the proximal colon of anaesthetized rabbits. In this species, the parasympathetic innervation of the proximal colon originates from the vagus nerves. The action of methoctramine and 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP) was studied on excitatory junction potentials (EJPs), and on inhibitory junction potentials (IJPs) elicited in smooth muscle cells by stimulating parasympathetic efferents. The effects of the same drugs on spontaneous spiking activity were also investigated. The EJPs either decreased or disappeared after intra-arterial (i.a.) administration of 4-DAMP (45 pg to 450 ng). In the presence of 4-DAMP, further intravenous (i.v.) administration of pirenzepine (0.1 mg.kg-1) had facilitatory effects on the inhibitory pathway, i.e., after abolition of the EJPs, vagal stimulation elicited IJPs. With the highest dose of 4-DAMP, vagal stimulation immediately elicited IJPs the amplitude of which still increased after pirenzepine. In the presence of 4-DAMP, the spontaneous spike discharge was not noticeably altered. Methoctramine (0.37 to 75 micrograms, i.a. or 50 micrograms to 0.2 mg.kg-1, i.v.) increased the amplitude of the EJPs, whereas it decreased that of the IJPs. In addition, at the same doses, it either initiated or increased spike discharges that were not altered by pirenzepine up to 0.2 mg.kg-1, i.v. The so-called rebound excitation occurring after IJPs was not affected by methoctramine. No change in the EJP or IJP amplitude was observed with gallamine at sufficiently high doses to paralyse striated muscles (up to 3 mg.kg-1.h-1). It is concluded that the parasympathetic excitatory pathway to smooth muscle is blocked by 4-DAMP, whereas it is facilitated by methoctramine. 4-DAMP has no effect on the inhibitory pathway which is strongly depressed by methoctramine; however, the fact that these two drugs have opposite effects indicates that 4-DAMP and methoctramine may act on different muscarinic receptor subtypes. In addition, the facilitatory effects of pirenzepine on IJPs observed in animals pre-treated with 4-DAMP, indicates that the latter drug may act on non-M1 and non-M2 (presumably M3) muscarinic receptors. Methoctramine acts on non-M1 and non-M3 (presumably M2) receptors. The spike discharge induced by methoctramine is presumably due to an increased release of acetylcholine, and possibly also of a non-cholinergic transmitter which has excitatory effects on smooth muscle, the identification of which requires further investigations.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究的目的是阐明非M1毒蕈碱受体在体内结肠运动的外在和内在神经控制中的作用。实验在麻醉兔的近端结肠上进行。在该物种中，近端结肠的副交感神经支配起源于迷走神经。研究了甲溴东莨菪碱和4-二苯基乙酰氧基-N-甲基哌啶甲基溴（4-DAMP）对兴奋性接头电位（EJP）以及刺激副交感传出神经在平滑肌细胞中引发的抑制性接头电位（IJP）的作用。还研究了相同药物对自发峰电位活动的影响。动脉内（i.a.）给予4-DAMP（45 pg至450 ng）后，EJP要么降低要么消失。在存在4-DAMP的情况下，进一步静脉内（i.v.）给予哌仑西平（0.1 mg·kg-1）对抑制性通路有促进作用，即EJP消失后，迷走神经刺激引发IJP。使用最高剂量的4-DAMP时，迷走神经刺激立即引发IJP，其幅度在哌仑西平作用后仍会增加。在存在4-DAMP的情况下，自发峰电位发放没有明显改变。甲溴东莨菪碱（0.37至75微克，i.a.或50微克至0.2 mg·kg-1，i.v.）增加EJP的幅度，而降低IJP的幅度。此外，在相同剂量下，它要么引发要么增加峰电位发放，静脉内给予高达0.2 mg·kg-1的哌仑西平对此无影响。IJP后出现的所谓反弹兴奋不受甲溴东莨菪碱影响。使用足够高剂量的加拉明使横纹肌麻痹（高达3 mg·kg-1·h-1）时，未观察到EJP或IJP幅度的变化。结论是，4-DAMP阻断了副交感神经对平滑肌的兴奋性通路，而甲溴东莨菪碱则促进该通路。4-DAMP对抑制性通路无作用，而该通路被甲溴东莨菪碱强烈抑制；然而，这两种药物具有相反作用这一事实表明，4-DAMP和甲溴东莨菪碱可能作用于不同的毒蕈碱受体亚型。此外，在预先用4-DAMP处理的动物中观察到哌仑西平对IJP有促进作用，这表明后一种药物可能作用于非M1和非M2（可能是M3）毒蕈碱受体。甲溴东莨菪碱作用于非M1和非M3（可能是M2）受体。甲溴东莨菪碱诱导的峰电位发放可能是由于乙酰胆碱释放增加，也可能还由于一种对平滑肌有兴奋作用的非胆碱能递质释放增加，其鉴定需要进一步研究。（摘要截短至400字）
