Sensitizing effect of tacrine on M-cholinergic receptors in gastric smooth muscle of rats.

AIM: To find if tacrine exerts a sensitizing effect on the cholinergic receptors of gastric smooth muscles, and study some of the mechanisms inducing it and measure the relative intensity of tacrine's effects on contractile activity. MATERIAL AND METHODS: Isometric recording of the mechanical activity of gastric smooth muscle preparations; determination of acetyl-cholinesterase activity in smooth-muscle tissue homogenates using Ellman's method. RESULTS: We found that the threshold concentration for tacrine not reducing the acetylcholinesterase activity and not having an effect on the smooth muscle preparations was 1 x 10(-8) mol/l. This concentration, however, significantly increased the acetylcholine-induced contraction compared with the controls, after the smooth-muscle tissue was incubated for 60 or 100 min. Treating smooth-muscle preparations with tacrine in a concentration of 5 x 10(-6) mol/l triggered a contraction induced by the drug's anti-cholinesterase activity. A secondary contraction was induced after 38.6 +/- 5.6 min. There was no secondary contraction after the control acetylcholine-induced effect. Atropine (1 x 10(-6) mol/l) inhibits this effect. Preliminary treatment of smooth muscle preparations with hexamethonium (1 x 10(-6) mol/l) did not change significantly the intensity of the first phase of tacrine-induced contraction and shifted in time the appearance of the second contractile phase. CONCLUSION: Tacrine has a sensitizing effect on M-cholinergic receptors; it occurs after a long incubation of the gastric smooth muscles with the drug and is manifested as a secondary contraction which is shifted in time and is significantly inhibited by atropine.

Calcium-independent tacrine-induced relaxation of rat gastric corpus smooth muscles.

Tacrine, a non-competitive reversible acetylcholinesterase and butyrylcholineserase inhibitor, caused a concentration-dependent tonic contraction of gastric smooth muscle preparations in the concentration range 1 x 10(-7) mol/L - 1 x 10(-5) mol/L, whereas concentrations higher than 2 x 10(-5) mol/L induced a biphasic effect; a short-time contraction was followed by a prolonged relaxation. To shed some light on the mechanism underlying this untypical relaxation, the amplitude of mechanical reactions caused by tacrine were compared with those of tacrine in the presence of atropine, ipratropium, metrifonate, TTX, nifedipine, D-600, caffeine, apamin, and charybdotoxin. The results obtained revealed that the relaxation was neither cholinergic in nature, nor mediated by the influence of the drug on intramural neuronal structures. It was not influenced by processes inducing changes in cytosolic Ca2+ levels. This assumption was confirmed by experiments with permeabilized muscle preparations that were pre-contracted in a solution with pCa 5.5. Tacrine relaxed the smooth muscles in spite of the constant intracellular Ca2+ concentration resulting from the permeabilization. These findings argue that tacrine at concentrations higher than 2 x 10(-5) mol/L has a desensitizing effect on the contractile apparatus of gastric corpus smooth muscle preparations towards Ca2+.

Non-anticholinesterase, non-cholinergic effect of tacrine on gastrointestinal smooth muscle tissues of rat.

INTRODUCTION: Tacrine is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. The drug also has an effect on a number of tissues and organs that are not targets of its therapeutical action in this disease. The gastrointestinal tract is one such affected organ. AIM: To investigate the in vitro effects of tacrine on rat stomach smooth muscles and determine the correlation between the anticholinesterase activity of the drug and the provoked smooth muscle mechanical responses. METHODS: The acetylcholinesterase activity was determined spectrophotometrically in tissue homogenates by the Ellman's method. Spectrophotometer "Cary 1" was used. The contraction activity of smooth muscle strips (11-12 mm long and 1.5-2 mm wide) from the gastric corpus was measured isometrically with Microtechna (Czech Republic) amplifier and recorded by Linseis (Germany) recorder. RESULTS: The results showed significant increase in the tacrine-induced contractions concurrent with reduction of the acetylcholinesterase activity within the concentration range of 10(-7)-10(-5) mol/l. The tendencies of development of both processes showed a high level of correlation (>0.99). Tacrine-induced contractions were inhibited significantly with atropine, ipatropium and hexametonium. They had a cholinergic character and most likely were due to endogenous acetylcholine accumulated as a result of inhibition of cholinesterase activity. An opposite tendency (correlation = - 0.98) was observed at tacrine concentrations of > or = 5.10(-5) mol/l: the decrease in the enzyme activity coincided with relaxation of muscle preparations. CONCLUSIONS: The analysis of the results suggests that the observed relaxation is non-anticholinesterase and non-cholinergic.

In vivo and in vitro study of the influence of the anticholinesterase drug galantamine on motor and evacuative functions of rat gastrointestinal tract.

Galantamine is efficacious for vascular dementia and Alzheimer's disease. Its application leads to some negative gastrointestinal side effects. The present study observes galantamine-induced influence on gastrointestinal motility of rats and its effects on isolated gastrointestinal smooth muscles. The gastrointestinal tract was studied by X-ray contrast examination. Functional disturbances were observed: hypertonia, increased stomach and ileal peristalsis activity, accelerated intestinal passage. In vitro, the drug caused tonic contractions in smooth muscle preparations and increased the gastric and ileal phasic amplitude. The jejunal smooth muscle strips demonstrated an opposite tendency. The reactions were a result of the interaction of galantamine-accumulated endogenic acetycholine with M- and N-acetylcholine receptors. The tonic effects were influenced in varying degree by atropine and ipratropium, whereas the phasic by atropine, ipratropium, hexametonium and methysergide. In conclusion, the in vitro effects registered satisfactorily explain in vivo examined galantamine-induced changes in the gastrointestinal tract of the treated rats and can be considered as main cause for development of such changes.