INTRODUCTION: Tacrine is an acetylcholinesterase inhibitor. It has an indirect cholinomimetic effect inducing contractions of the gastric smooth muscles. The contractions are related to the effect of the accumulated acetylcholine in tissues on the respective choline receptors. There is a well defined direct correlation between tacrine concentrations and the inhibition of cholinesterase activity. That suggest simultaneous increase of the strength of tacrine-induced contractions. Instead, at concentrations above 1 x 10(-5) mol/l, tacrine causes permanent relaxation with yet unknown causing mechanism. AIM: The aim of this study was to investigate if tacrine induces reduction of calcium ions through chelation and/or inhibits directly calmodulin's participation in the contractile processes, thus causing smooth muscle relaxation which is not characteristic of a typical acetylcholinesterase blocker. METHODS: The contractile activity of smooth muscle preparations was measured isometrically with a Microtechna (Czech Republic) amplifier and recorded by a Linseis (Germany) recorder. The absorption electron spectrum of tacrine (1 x 10(-4) mol/l) was determined with a Cary 1 (Varian, Australia) spectrophotometer. The concentration of ionized CaCa2+ was measured with the ISE-block of a clinical-chemical analyzer Konelab 60 (Finland). RESULTS: The presence of Ca2+ (10(-2) mol/l) does not alter tacrine characteristic absorption spectrum at pH values corresponding to the SM cell cytosolic pH. The presence of 1 x 10(-4) mol/l tacrine does not affect Ca2+ concentration in the Krebs solution (pH = 7.4). In the presence of trifluoperazine (a calmodulin blocker) 1 x 10(-4) mol/l tacrine causes relaxation which is commensurable with that in the controls. CONCLUSIONS: Tacrine-induced smooth muscle relaxation is not a result of the reduction of the effective Ca2+ concentrations as a result of chelation between tacrine and Ca2+ and it is not related to the tacrine effects on calmodulin.
INTRODUCTION:Tacrine is an acetylcholinesterase inhibitor. It has an indirect cholinomimetic effect inducing contractions of the gastric smooth muscles. The contractions are related to the effect of the accumulated acetylcholine in tissues on the respective choline receptors. There is a well defined direct correlation between tacrine concentrations and the inhibition of cholinesterase activity. That suggest simultaneous increase of the strength of tacrine-induced contractions. Instead, at concentrations above 1 x 10(-5) mol/l, tacrine causes permanent relaxation with yet unknown causing mechanism. AIM: The aim of this study was to investigate if tacrine induces reduction of calcium ions through chelation and/or inhibits directly calmodulin's participation in the contractile processes, thus causing smooth muscle relaxation which is not characteristic of a typical acetylcholinesterase blocker. METHODS: The contractile activity of smooth muscle preparations was measured isometrically with a Microtechna (Czech Republic) amplifier and recorded by a Linseis (Germany) recorder. The absorption electron spectrum of tacrine (1 x 10(-4) mol/l) was determined with a Cary 1 (Varian, Australia) spectrophotometer. The concentration of ionizedCaCa2+ was measured with the ISE-block of a clinical-chemical analyzer Konelab 60 (Finland). RESULTS: The presence of Ca2+ (10(-2) mol/l) does not alter tacrine characteristic absorption spectrum at pH values corresponding to the SM cell cytosolic pH. The presence of 1 x 10(-4) mol/l tacrine does not affect Ca2+ concentration in the Krebs solution (pH = 7.4). In the presence of trifluoperazine (a calmodulin blocker) 1 x 10(-4) mol/l tacrine causes relaxation which is commensurable with that in the controls. CONCLUSIONS:Tacrine-induced smooth muscle relaxation is not a result of the reduction of the effective Ca2+ concentrations as a result of chelation between tacrine and Ca2+ and it is not related to the tacrine effects on calmodulin.