caa a22 4500 46907812X CHVBK 20180323132941.0 cr unu---uuuuu 170328e19920901xx s 000 0 eng 10.1007/BF00173550 doi (NATIONALLICENCE)springer-10.1007/BF00173550 Enantioselectivity of asocainol studied at different conditions: a novel approach to check the feasibility of molecular models of antiarrhythmic drug action [Elektronische Daten] [J. Gödicke, S. Herzig, A. Mescheder, K. Mohr, F. Steinke] Summary: In terms of the "guarded receptor” hypothesis, changes in potency of Na+ channel blocking drugs reflect alterations in drug access to and/or egress from a compartment facing a binding site with constant affinity. Potency is therefore assumed to be determined by changes in drug diffusion, its mobility in the electric field, protonation etc. Hence, the potencies of enantiomers, i. e. compounds with identical physicochemical properties, should be influenced in a parallel manner by the condition. To test this prediction, actions of the enantiomers of the stereoselective antiarrhythmic drug asocainol were compared at various membrane potentials and stimulus frequencies. Several experimental models indicative of Na+ channel block were used: the elevation of the rectangular pulse stimulation threshold (RPT) and the suppression of alternating-current induced arrhythmia (ACT) were studied in guinea-pig atria. The reduction of the upstroke velocity of action potentials was measured in guinea-pig papillary muscles. The inhibition of whole-cell Na+ currents was investigated in isolated guinea-pig ventricular myocytes. In all these assays, (+)-asocainol was more potent than the (-)-enantiomer. Lowering the membrane potential and/or increasing the stimulus frequency enhanced the effects of both enantiomers. However, over a certain range of conditions, the potency of (+)-asocainol was more markedly affected than that of (-)-asocainol, indicating that the eudismic ratio between potencies of the two drugs is not constant. Accordingly, these findings are inconsistent with the guarded receptor hypothesis. Springer-Verlag, 1992 Asocainol nationallicence Enantioselectivity nationallicence Guarded receptor hypothesis nationallicence Modulated receptor hypothesis nationallicence Na+ channel blockade nationallicence Gödicke J. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut Herzig S. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut Mescheder A. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut Mohr K. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut Steinke F. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/3(1992-09-01), 345-351 0028-1298 346:3<345 1992 346 210 https://doi.org/10.1007/BF00173550 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00173550 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Gödicke J. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut NATIONALLICENCE 700 1- Herzig S. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut NATIONALLICENCE 700 1- Mescheder A. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut NATIONALLICENCE 700 1- Mohr K. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut NATIONALLICENCE 700 1- Steinke F. Department of Pharmacology, University of Kiel, Hospitalstrasse 4, W-2300, Kiel, Federal Republic of Germany aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/3(1992-09-01), 345-351 0028-1298 346:3<345 1992 346 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer