Effects of alaproclate, potassium channel blockers, and lidocaine on the release of 3H-acetylcholine from the guinea-pig ileum myenteric plexus.
The guinea-pig ileum longitudinal muscle-myenteric plexus preparation, preincubated with 3H-choline or 3H-noradrenaline, was mounted in an organ bath and superfused with Tyrode's solution. Alaproclate (2-(4-chlorophenyl)-1,1-dimethyl 2-aminopropanoate) (0.01-0.5 mmol/l) reduced (IC50 = 0.1 mmol/l) and at about 0.5 mmol/l completely blocked the electrically evoked 3H-acetylcholine secretion. The depressing effect of alaproclate (0.2 mmol/l) was not counteracted by atropine (0.01, 1 or 10 mumol/l), hexamethonium (0.1 mmol/l), phentolamine (1 mumol/l) yohimbine (1 mumol/l), haloperidol (1 mumol/l), 8-phenyltheophylline (10 mumol/l), cyproheptadine (1 mumol/l), metitepine (1 mumol/l), bicuculline (10 mumol/l), picrotoxinin (0.1 mmol/l), forskolin (25 mumol/l), 3-isobutyl-1-methylxanthine (5 mmol/l), nifedipine (1 mumol/l), verapamil (1 mumol/l), dilitiazem (1 mumol/l), high calcium (6 mmol/l), high potassium (10 or 15 mmol/l), tetraethylammonium (2 mmol/l), 4-aminopyridine (0.5 mmol/l), apamin (0.5 mumol/l), barium (0.5 mmol/l) or quinine (0.1 mmol/l). Among the potassium channel blockers tested only quinine (at 0.5 or 1 mmol/l), in the same manner as lidocaine, reduced the evoked secretion of 3H-acetylcholine. The results are in agreement with the hypothesis that the effect of alaproclate on the evoked 3H-acetylcholine secretion is not mediated by a neurotransmitter receptor, or a potassium channel sensitive to tetraethylammonium, 4-aminopyridine, apamin, or barium or quinine, but is due to a local anaesthetic effect. In contrast to the evoked secretion, the spontaneous release of 3H-acetylcholine was enhanced by high concentrations of alaproclate (0.4-1 mmol/l). The mechanism underlying the effect of alaproclate on the spontaneous release remains to be established. Alaproclate (0.25 or 0.5 mmol/l) also enhanced the spontaneous release and reduced the electrically evoked 3H-noradrenaline secretion.
Alberts
P
P
Division of Experimental Medicine, Swedish Defence Research Establishment, Umeå.
Ogren
S O
SO
D000109:Acetylcholine / Q000378:metabolism*; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D009197:Myenteric Plexus / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D013564:Sympathetic Nervous System / Q000187:drug effects; D014316:Tritium
D000928:Antidepressive Agents; D015221:Potassium Channels; D014316:Tritium; D008012:Lidocaine; C025293:alaproclate; D000109:Acetylcholine; D000409:Alanine; D009638:Norepinephrine