Sylvester E. Vizi

Evidence that acetylcholine released by gastrin and related polypeptides contributes to their effect on gastrointestinal motility.

Abstract Gastrin- and cholecystokinin-like polypeptides have been found to release acetylcholine from the Auerbach plexus of longitudinal muscle strips of guinea pig ileum. The evidence is consistent with the view that contractions of intestine in response to these peptides are due to the acetylcholine released. Tetrodotoxin inhibited actions of peptides both on acetylcholine release and on mechanical responses of intestine; however, hexamethonium failed to affect their actions, indicating that their site of action is situated on non-nicotinic receptors of ganglionic cells. C-terminal octapeptide amide of cholecystokinin-pancreozymin and caerulein produced significant acetylcholine release in concentrations as low as 9 × 10 −10 and 7.5 × 10 −10 M, respectively. Human gastrin I was much less effective, its threshold concentration being 7 × 10 −8 M. Both exogenous and endogenous noradrenaline reduced both the acetylcholine release and the contractions of longitudinal muscle produced by peptides. Noradrenaline acted at a presynaptic site and its action was mediated through α receptors. It is concluded that gastrointestinal hormones may play a role as hormonal factors in regulating gastrointestinal motility, and their effect is continuously controlled by the tonic activity of the sympathetic nervous system which reduces acetycholine release.

N-type calcium channels are involved in the dopamine releasing effect of nicotine

Mouse striatum was incubated with [3H]dopamine ([3H]DA) and superfused with and the tritium efflux induced by nicotine, electrical stimulation, or simultaneous nicotine and electrical stimulation was measured, to characterize the role of different Ca2+ channels in the transmitter release. Nicotine stimulation and electrical stimulation exerted additive effects on tritium efflux. Separation of the released radioactivity on alumina columns indicated that nicotine or electrical stimulation increases the release of [3H]DA and that the outflow of3H-labeled metabolites was similar with the two different stimulation procedures. Removal of Ca2+ from the superfusate resulted in a marked reduction in the tritium release evoked by nicotine, whereas the electrical stimulation-evoked tritium release was completely dependent on external Ca2+. The L-and N-type calcium channel blockers omega-conotoxin GVIA and Cd2+ inhibited the tritium release from the striatum evoked by either nicotine or electrical stimulation, whereas the L-type and T-type channel blockers diltiazem and Ni2+ did not alter release of [3H]DA. We conclude that N-type voltage-sensitive Ca2+ channels participate in striatal dopamine release, and we speculate that nicotinic receptor-operated ion channels permeable to cations such as Ca2+ and N-type voltage-sensitive calcium channels may simultaneously open up, and they additively increase free intracellular Ca2+ concentration.

Physiological release of striatal acetylcholine (in vivo): effect of somatostatin on dopaminergic-cholinergic interaction

The effects of somatostatin (SOM) on the release of acetylcholine (ACh) and dopamine (DA) from striatum of freely moving rats were studied by transversal microdialysis. Acetylcholine (ACh) and dopamine (DA) were detected by high performance liquid chromatography (HPLC) with electrochemical detection. Somatostatin (0.1, 0.5 and 1 microM), administered locally through the microdialysis probe to the striatum, was able to release dose-dependently ACh from the cholinergic neurons of the striatum. The increase in the extracellular levels of ACh produced by 1 microM SOM in the striatum reached a maximum of 200%. ACh-releasing effect of SOM was completely inhibited by tetrodotoxin indicating that neuronal firing is involved in its effect. Local infusion of sulpiride, 10 microM, D(2) receptor antagonist, potentiated (about 100%) the SOM (1 microM)-induced release of ACh. SOM, 1 microM, was more effective in enhancing the release of ACh in the striatum (two-fold increase) after degeneration of the nigrostriatal DA pathway with 6-hydroxydopamine (6-OHDA) (250 microg/animal, i.c.v.). The D(2) receptor agonists bromcriptine, 10 microM, or apomorphine, 10 microM, completely antagonize SOM-induced release. SOM, 1 microM, enhanced the release of DA (about 400%). These findings indicate that SOM is capable of releasing both ACh and DA in the striatum, however, its effect on ACh release is partially masked unless the D(2) receptor-mediated tonic inhibitory effect of released DA from the nigro-striatal pathway is attenuated.

The conversion of met-enkephalin-Arg6, Phe7 to met-enkephalin in rabbit ear artery

We studied the opioid agonist activities of met-enkephalin-Arg6, Phe7 heptapeptide (ME-A,P) and its D-Ala2-analogue in several isolated organs including rabbit ear artery (ART), guinea-pig ileum (GPI) mouse-, rat and rabbit vas deferens preparation. Both heptapeptides followed the in vitro activity pattern of met-enkephalin (ME). There was a significant parallelism in the sensitivity of ART and mouse vas deferens to opioid peptides. In ART, ME-A,P must be converted by a captopril sensitive enzyme to exert opioid agonist action. Incubation of heptapeptide with membranes prepared from rabbit ear artery revealed the captopril-sensitive enzymic conversion of ME-AP to ME as detected by high voltage paper electrophoresis.

Azaberbene Derivatives as α2A‐Adrenoceptor Antagonists

The synthesis of octahydro‐8H‐isoquino[2, 1‐g][1, 6]naphthyridine derivatives 2a‐f was carried out.These newcompounds are selective α2A‐adrenoceptor antagonists.