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

Abstract

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+.

Comparative X-Ray study of galantamine and tacrine on the evacuatory function of rat gastrointestinal tract

“…However, the tacrine-treated animals showed some specific reactions, namely, fornical and caecal relaxation, antral contraction, and a lack of statistically significant peristaltic activity. The combination of tacrin-induced non-anticholinesterase and noncholinergic tonic relaxation and the inhibition of the phasic mechanical activity [30] combined with the contractile effects of acummulated actylcholine can account for the changes that we observed. In addition, there are likely variations in the thresholds for these acetylcholinesterase-indepent effects in different areas of the GI tract [31].…”

Participation of cAMP in tacrine-induced gastric smooth muscle relaxation

“…Our previous studies have shown that the relaxation effect of tacrine at concentrations higher than 2×10 -5 mol/l had no related with modulation of cytosolic Са 2+ level of treated SM cells but probably with desensitization of the SM contractile apparatus to Са 2+ [14]. The sensitization (desensitization) states of the contractile apparatus and the resulting SM contraction (relaxation) are usually a function of the ratio between the activity of myosin light-chain kinase (MLCK) and myosin light chain phosphatase (MLCP).…”

“…Drugs that inhibit muscarinic receptors on gastrointestinal smooth muscles and nicotinic receptors on enteric nerve cells do not influence the amplitude of tacrine-induced relaxation [13]. This relaxation was not affected by preliminary treatments of muscle strips with tetrodotoxin (ТТХ), a nerve action potentials blocker, potassium channel blockers (charybdotoxin, apamin, tetraethylammonium, and 4-aminopyridine) [14], and Ca 2+ antagonists [15]. Therefore, this relaxing effect of tacrine is Ca 2+ -independent.…”

“…Therefore, this relaxing effect of tacrine is Ca 2+ -independent. It is a result from the direct action of tacrine over the contractile apparatus of the gastrointestinal smooth muscles [14]. When applied in vivo (daily dose 0.5 mg/kg) the drug significantly influences the motility of GI tract, causing hypotension, inhibited peristaltic activity and retarded evacuatory kinetics [12,16].…”

Tacrine-induced tachyphylaxis in gastric smooth muscles

“…Our previous investigations have shown that tacrine exerts some of its non-anticholinesterase effects on gastric SMs by increasing the cAMP level, stimulating adenylate cyclase (AC) and activating the intracellular pathway: сАМР -protein kinase А (РKА) -myosin light chain protein kinase (MLCPK) -the contractile apparatus of SMs [11] The effect of triggering this mechanism occurs as a Са 2+ -independent SM relaxation [12] that dominates the behavior of SM preparations at concentrations higher than 1×10 -5 mol/l. сАМР and РKА, respectively, are important signal molecules in the body of humans and animals, which are involved in many physiological and pathophysiological processes.…”