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

Abstract

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 vitrousing a spectrophotometric kinetic assay with acetylthiocholine (ASCh) as substrate. Sotalol concentrations in the assays varied from 0.32 to 3.2m M. 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 (V max). Thus, D/ L-sotalol inhibition of serum ChE was of the competitive type (rate constant for reversible competitive inhibition: K i=0.51m M). In contrast, D/ Lsotalol 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 (K Mwith ASCh unchanged) indicating purely non-competitive inhibition kinetics (rate constant of reversible non-competitive inhibition: K i′=0.44m M). D/ L-sotalol inhibition of erythrocyte AChE was of mixed competitive/non-competitive type (K i=0.31m M, K i′=0.49m M). 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 (15μ M) and experimental animals (dogs: 18μ M; rats: 260μ M) as well as maximal myocardial concentrations of the substance (dogs: 46μ M; rats: 478μ M) 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 vivomay contribute to both the well known antiarrhythmic potential and proarrhythmic side effects of the compound.