[Modulatory mechanisms involved in the parasympathetic excitatory neuro-effector transmission in the airway and gastrointestinal tracts--perspective for a new drug creation].
It is generally considered that dominant excitatory control of airway and gastrointestinal tract is exerted by the parasympathetic nervous system, and the transmitter output from the nerve terminals, mainly acetylcholine (ACh), is modulated in many ways for example by ACh itself, prostaglandins E series (PGE) neuropeptides and nitric oxide (NO). These modulations are probably due to the suppression of high-voltage-activated calcium channels in the nerve terminals, since, for example, ACh or prostaglandin E1 & E2 selectively suppressed both the N- and R-type Ca2+ currents, through M2 muscarinic and EP3-receptors, respectively in paratracheal ganglion cells. Parasympathetic nervous system also releases nonadrenergic-noncholinergic (NANC) inhibitory neurotransmitters in addition to ACh. The threshold level for ACh and NO release, for example, is almost identical, thereby suggesting the possible interactions between NO and ACh at the post-junctional cites, in addition to the prejunctional inhibitory action of NO to suppress ACh release from the nerve terminal. In this context, NO-donors, including SNAP or Cys-NO, reduced the amplitude of carbachol-induced Ca(2+)-dependent Cl- currents (I infinity h, I alpha(Ca)) dose-dependently (IC50: about 10 microM) in the cat tracheal myocytes, and similar inhibition was also exerted by dibutyryl cGMP (db-cGMP). However, two structurally distinct types of G-kinase inhibitor, H-8 (2.5 microM) and KT5823 (1 microM) failed to counteract the inhibitory effects of SNAP or db-cGMP. Another G-kinase-specific inhibitor, (Rp)-8-pCPT-cGMPS, itself caused a marked reduction in I infinity h, thereby indicating that inhibition of I infinity h by NO donors involves a cGMP-dependent but G-kinase-independent mechanism. All these experimental facts taken together indicate that there are pre- and post-junctional "brakings" in the excitatory parasympathetic neuro-effector transmission. Furthermore, in the gastrointestinal tract, Z-338, a newly synthetized gastroprokinetic agent, stimulates gastrointestinal motility through inhibition of the pre-junctional braking system through inhibition of M1 receptors. Such a drug may be useful to control the respiratory and gastrointestinal smooth muscles.
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Department of Pharmacology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
D000818:Animals; D002415:Cats; D004064:Digestive System / Q000294:innervation*; D004285:Dogs; D010275:Parasympathetic Nervous System / Q000502:physiology*; D012137:Respiratory System / Q000294:innervation*; D009435:Synaptic Transmission / Q000502:physiology*