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PubMedDate not supplied

Indirect parasympathomimetic activity of the class III antiarrhythmic substance D/L-sotalol in vitro: reversible inhibition of cholinesterase isoenzymes from blood and the human central nervous system.

Inhibitory effects of the class III antiarrhythmic compound D/L-sotalol on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and the human caudate nucleus and on serum cholinesterase (ChE; EC 3.1.1.8) were studied in vitro using a spectrophotometric kinetic assay with acetylthiocholine (ASCh) as substrate. Sotalol concentrations in the assays varied from 0.32 to 3.2 mM. All isoenzymes studied were inhibited by D/L-sotalol in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that D/L-sotalol reduced substrate affinity (apparent Michaelis constant, KM, increased) of serum ChE, but did not change the enzyme's maximal rate of ASCh hydrolysis (Vmax). Thus, D/L-sotalol inhibition of serum ChE was of the competitive type (rate constant for reversible competitive inhibition: Ki = 0.51 mM). In contrast, D/L sotalol reduced the maximal reaction velocity of the AChE isoenzyme from the central nervous system (caudate nucleus), but had no influence on substrate affinity of the enzyme (KM with ASCh unchanged) indicating purely non-competitive inhibition kinetics (rate constant of reversible non-competitive inhibition: Ki = 0.44 mM). D/L-sotalol inhibition of erythrocyte AChE was of mixed competitive/non-competitive type (Ki = 0.31 mM, Ki = 0.49 mM). Non-competitive D/L-sotalol inhibition of caudate nucleus AChE and the non-competitive component of erythrocyte AChE inhibition cannot be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Peak D/L-sotalol plasma levels as described in the literature for both humans (15 microM) and experimental animals (dogs: 18 microM; rats: 260 microM) as well as maximal myocardial concentrations of the substance (dogs: 46 microM; rats: 478 microM) are in the range of about 2% to 100% of the sotalol inhibition rate constants determined in the present paper for cholinesterase isoenzymes in vitro. Thus, D/L-sotalol inhibition of ACh hydrolysis in vivo may contribute to both the well known antiarrhythmic potential and proarrhythmic side effects of the compound.

Animals↗
PubMedDate not supplied

Indirect parasympathomimetic activity of metoclopramide: reversible inhibition of cholinesterases from human central nervous system and blood.

Inhibitory effects of the dopamine D2-receptor antagonistic benzamide compound metoclopramide (MCP) on acetylcholinesterase (AChE; EC 3.1.1.7) isoenzymes of both erythrocytes and human caudate nucleus and on human serum cholinesterase (ChE; EC 3.1.1.8) were studied in vitro using a spectrophotometric assay with acetylthiocholine (ASCh) as substrate. MCP concentrations in the assays varied from 0.30 microM to 0.15 mM. All isoenzymes studied were inhibited by metoclopramide in a concentration-dependent manner. MCP inhibition of AChE and ChE isoenzymes was not time-dependent and of the reversible type. Double reciprocal plots of the reaction velocity against varying ASCh concentrations revealed that, for AChE isoenzymes of erythrocytes and of the caudate nucleus, MCP reduced both maximal reaction velocity (Vmax) and substrate affinity (apparent Michaelis constant, KM, increased). Thus, MCP inhibition of both AChE isoenzymes was of mixed competitive/non-competitive type. MCP constants for reversible competitive (Ki) and non-competitive (Ki) inhibition could be determined for erythrocyte AChE (Ki = 10 microM; Ki = 70 microM) and caudate nucleus AChE (Ki = 9.3 microM; Ki = 82 microM). In contrast to MCP inhibition of AChE isoenzymes, the type of reversible MCP inhibition of human serum ChE depended on substrate concentration. If substrate concentration exceeded 0.2 mM, MCP inhibition was of mixed competitive/non-competitive type (Ki = 0.19 microM; Ki = 1.4 microM). MCP inhibition was of uncompetitive type, if substrate concentration was below 0.2 mM (Ki(u) = 1.0 microM). The mixed-type MCP inhibition of cholinesterase isoenzymes, because of its non-competitive component, can only partially be overcome by increased concentrations of the cholinergic transmitter acetylcholine (ACh). Since, with intravenous infusions, peak MCP plasma concentrations in humans reach 4 microM, MCP inhibition of ACh hydrolysis in vivo may contribute both to prokinetic and anti-emetic actions of the substance and to its extrapyramidal side effects.

Acetylcholinesterase↗
PubMed1984

Amino acid composition of salivary protein secreted by the parotid glands of rats in response to parasympathomimetic and sympathomimetic drugs.

Although the total protein concentration in the saliva varied markedly, depending on the nature of the stimulus, the proportions of the amino-acid residues were independent on the nature of the stimuli, where they were cholinergic, adrenergic or dopaminergic. However, the difference in protein composition of saliva previously shown in chronically isoprenaline-treated rats electrophoretically could be determined by amino-acid analysis.

Amino Acids↗