Excitatory and inhibitory effects of second-generation cholinesterase inhibitors on rat gastrointestinal transit

We investigated the influence of increasing oral doses of second generation acetylcholinesterase inhibitors (AChEI) such as tacrine (0.25, 0.5, 1, 2, 3, 4, 10, and 20 mg kg(-1)), eptastigmine (0.5, 4, 8, 12, 20 and 40 mg kg(-1)) and E2020 (0.18, 0.25, 0.5, 1, 2, 3, 4 and 10 mg kg(-1)) on the distance travelled by a charcoal meal administered 30 min after each compound, in comparison with physostigmine (0.5, 1, 2, 4, 8 and 12 mg kg(-1)). An inverted U regression was observed with a significant parabola between the centimetres travelled and the log of the doses for all AChEI. The maximal stimulating doses (mg kg(-1)) were 2 for physostigmine, 4 for eptastigmine, 3 for tacrine and E2020, while the inhibitory doses were 12 for physostigmine, 40 for eptastigmine, 20 for tacrine and 10 for E2020. The stimulating and inhibiting effects on gastrointestinal propulsion were significantly reversed by 0.25 mg kg(-1) of scopolamine hydrobromide. A dose of scopolamine hydrobromide (0.06 mg kg(-1)) or methylbromide (0.25 mg kg(-1)), pirenzepine dihydrochloride (0.25 mg kg(-1)) and mecamylamine hydrochloride (0.5 mg kg(-1)), which per se did not affect gastrointestinal propulsion, antagonized both the stimulating and inhibitory effect of eptastigmine. Thus, the biphasic effect is peripherally mediated through both muscarinic (at least M-1) and nicotinic receptors.