File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Effects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle

TitleEffects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscle
Authors
Issue Date1991
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00210/index.htm
Citation
Naunyn-Schmiedeberg's Archives Of Pharmacology, 1991, v. 344 n. 6, p. 662-673 How to Cite?
AbstractDisopyramide, a Class Ia antiarrhythmic drug, is clinically used as a racemic mixture; R(-)disopyramide and S(+)disopyramide. The major metabolite in man is desisopropyldisopyramide: R(-)desisopropyldisopyramide and S(+)desisopropyldisopyramide. The effects of the four compounds were compared on the electrophysiological characteristics of the guinea-pig papillary muscle using the standard microelectrode technique. At an external K+ concentration of 5.4 mmol/l and a stimulation frequency of 1 Hz, S(+)disopyramide (20 μmol/l) increased action potential duration(APD) by more than 18%, while it was diminished by 6% in the presence of R(-)disopyramide. Resting membrane potential amounted to -87.1 ± 0.5 mV (n = 14) and -85.6 ± 1.2 mV (n = 10), respectively. Also a small but significant difference in effect on the maximal rate of depolarization was observed, R(-)disopyramide being more potent, related with a slower recovery of the maximal rate of depolarization. The enantiomers of the metabolite appeared to be three times less potent than those of the parent drug in their effect on the maximal rate of depolarization. The characteristics of the enantiomers of the metabolite correlated with those of the parent drug: also the R(-)enantiomer was more potent in decreasing the maximal rate of depolarization and caused more shortening of the action potential than the S(+)enantiomer. Time constants for onset and recovery of/from rate dependent block of the maximal rate of depolarization were dependent upon the external K+ concentration, both for the enantiomers of the parent drug and those of the metabolite. Onset slowed down while recovery accelerated when external K+ was increased. Time constants were lower for the metabolite. When stimulation interval was shortened, the effect on the maximal rate of depolarisation increased. Only for the metabolite statistical significant stereoselective differences were observed at all stimulation intervals. The effects on the action potential duration were dependent upon stimulation interval; for all enantiomers the action potential duration tended to be relatively (% of control) higher at short stimulation intervals than at large stimulation intervals. The effect on the maximal rate of depolarization was also voltage dependent, but no significant differences were observed between the enantiomers, for the parent drug as well as for the metabolite.
Persistent Identifierhttp://hdl.handle.net/10722/171039
ISSN
2015 Impact Factor: 2.376
2015 SCImago Journal Rankings: 0.859
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorVanhoutte, Pen_US
dc.contributor.authorVereecke, Jen_US
dc.contributor.authorCarmeliet, Een_US
dc.contributor.authorVerbeke, Nen_US
dc.date.accessioned2012-10-30T06:11:56Z-
dc.date.available2012-10-30T06:11:56Z-
dc.date.issued1991en_US
dc.identifier.citationNaunyn-Schmiedeberg's Archives Of Pharmacology, 1991, v. 344 n. 6, p. 662-673en_US
dc.identifier.issn0028-1298en_US
dc.identifier.urihttp://hdl.handle.net/10722/171039-
dc.description.abstractDisopyramide, a Class Ia antiarrhythmic drug, is clinically used as a racemic mixture; R(-)disopyramide and S(+)disopyramide. The major metabolite in man is desisopropyldisopyramide: R(-)desisopropyldisopyramide and S(+)desisopropyldisopyramide. The effects of the four compounds were compared on the electrophysiological characteristics of the guinea-pig papillary muscle using the standard microelectrode technique. At an external K+ concentration of 5.4 mmol/l and a stimulation frequency of 1 Hz, S(+)disopyramide (20 μmol/l) increased action potential duration(APD) by more than 18%, while it was diminished by 6% in the presence of R(-)disopyramide. Resting membrane potential amounted to -87.1 ± 0.5 mV (n = 14) and -85.6 ± 1.2 mV (n = 10), respectively. Also a small but significant difference in effect on the maximal rate of depolarization was observed, R(-)disopyramide being more potent, related with a slower recovery of the maximal rate of depolarization. The enantiomers of the metabolite appeared to be three times less potent than those of the parent drug in their effect on the maximal rate of depolarization. The characteristics of the enantiomers of the metabolite correlated with those of the parent drug: also the R(-)enantiomer was more potent in decreasing the maximal rate of depolarization and caused more shortening of the action potential than the S(+)enantiomer. Time constants for onset and recovery of/from rate dependent block of the maximal rate of depolarization were dependent upon the external K+ concentration, both for the enantiomers of the parent drug and those of the metabolite. Onset slowed down while recovery accelerated when external K+ was increased. Time constants were lower for the metabolite. When stimulation interval was shortened, the effect on the maximal rate of depolarisation increased. Only for the metabolite statistical significant stereoselective differences were observed at all stimulation intervals. The effects on the action potential duration were dependent upon stimulation interval; for all enantiomers the action potential duration tended to be relatively (% of control) higher at short stimulation intervals than at large stimulation intervals. The effect on the maximal rate of depolarization was also voltage dependent, but no significant differences were observed between the enantiomers, for the parent drug as well as for the metabolite.en_US
dc.languageengen_US
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00210/index.htmen_US
dc.relation.ispartofNaunyn-Schmiedeberg's Archives of Pharmacologyen_US
dc.subject.meshAction Potentials - Drug Effectsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshDisopyramide - Metabolism - Pharmacologyen_US
dc.subject.meshElectric Stimulationen_US
dc.subject.meshElectrophysiologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshGuinea Pigsen_US
dc.subject.meshHeart - Drug Effects - Physiologyen_US
dc.subject.meshKineticsen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Potentials - Drug Effectsen_US
dc.subject.meshPapillary Muscles - Drug Effectsen_US
dc.subject.meshStereoisomerismen_US
dc.titleEffects of the enantiomers of disopyramide and its major metabolite on the electrophysiological characteristics of the guinea-pig papillary muscleen_US
dc.typeArticleen_US
dc.identifier.emailVanhoutte, P:vanhoutt@hku.hken_US
dc.identifier.authorityVanhoutte, P=rp00238en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid1775199-
dc.identifier.scopuseid_2-s2.0-0026338741en_US
dc.identifier.volume344en_US
dc.identifier.issue6en_US
dc.identifier.spage662en_US
dc.identifier.epage673en_US
dc.identifier.isiWOS:A1991GW53900007-
dc.publisher.placeGermanyen_US
dc.identifier.scopusauthoridVanhoutte, P=7202304247en_US
dc.identifier.scopusauthoridVereecke, J=35847337900en_US
dc.identifier.scopusauthoridCarmeliet, E=7102374225en_US
dc.identifier.scopusauthoridVerbeke, N=7003555300en_US

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats