Enhancement of purinergic neurotransmission by galantamine and other acetylcholinesterase inhibitors in the rat vas deferens

• Published in: European journal of pharmacology Vol. 503; no. 1; pp. 191 - 201
• Main Authors: Caricati-Neto, Afonso, D'angelo, Luiz Carlos Abech, Reuter, Haydee, Hyppolito Jurkiewicz, Neide, G. Garcia, Antonio, Jurkiewicz, Aron
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25-10-2004; Elsevier
• Subjects: Acetylcholine - pharmacology; Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Cholinesterase Inhibitors - pharmacology; Drug Synergism; Electric Stimulation; Galantamine; Galantamine - pharmacology; In Vitro Techniques; Indans - pharmacology; Male; Medical sciences; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Pharmacology. Drug treatments; Phenylcarbamates - pharmacology; Physostigmine - pharmacology; Piperidines - pharmacology; Purinergic neurotransmission; Rats; Rats, Wistar; Receptors, Purinergic - drug effects; Rivastigmine; Stimulation, Chemical; Synaptic Transmission - drug effects; Tacrine - pharmacology; Vas deferens; Vas Deferens - drug effects; Vas Deferens - innervation; Galantamine; Purinergic neurotransmission; Vas deferens; Semen pathway; Rat; Enzyme; Benzazepine derivatives; Rodentia; Enzyme inhibitor; Esterases; Male genital duct; Antialzheimer agent; Acetylcholinesterase; Male genital system; Carboxylic ester hydrolases; Parasympathomimetic; Alkaloid; Vertebrata; Mammalia; Animal; Hydrolases; Anticholinesterase agent; Neurotransmission
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2004.09.034

Galantamine, a mild acetylcholinesterase inhibitor and an allosteric ligand of nicotinic receptors, enhanced in a concentration-dependent manner the amplitude of purinergic twitch contractions of the electrically stimulated rat vas deferens (0.2 Hz, 1 ms, 60 V). Other acetylcholinesterase inhibitors also increased the twitches, showing a hierarchy of potencies of galantamine>physostigmine>tacrine>rivastigmine=donepezil. The potentiations seem to be unrelated to the ability to inhibit acetylcholinesterase, since the hierarchy of potencies to block the enzyme in vas deferens was tacrine>physostigmine>rivastigmine>donepezil>galantamine. Acetylcholine also increased the twitches; such effect was produced by a low range of concentrations of acetylcholine (10
−10–10
−7 M). This facilitatory effect of acetylcholine on twitches was significantly potentiated by galantamine (10
−7–10
−6 M), but not by rivastigmine or donepezil. A striking enhancement of twitches was also caused by charybdotoxin, a blocker of high-conductance Ca
2+-activated K
+ channels, and by 4-aminopyridine, a non-specific blocker of K
+ channels; in addition, apamin, a blocker of small-conductance Ca
2+-activated K
+ channels, induced a lower potentiation. The antagonist mecamylamine (10
−7–10
−6 M) reduced by 80% the potentiation by galantamine, indicating the involvement of nicotinic receptors. Therefore, it is suggested that, besides an inhibition of acetylcholinesterase, some additional mechanisms, such as blockade of Ca
2+-dependent K
+ channels, or activation of nicotinic receptors of nerve terminals, might be involved in twitch potentiation. These results are relevant in the context of the clinical use of galantamine to improve cognition and behaviour in patients with Alzheimer's disease.