title: Positive and negative inotropic effects of DL-sotalol and D-sotalol in failing and nonfailing human myocardium under physiological experimental conditions.
abstract: BACKGROUND
  DL-Sotalol has class III antiarrhythmic activity through prolongation of the repolarization phase of the action potential as well as beta-adrenoceptor-blocking properties. Although the former effect was found to exert positive inotropic effects in animal experimental studies, the latter may be detrimental in heart failure due to negative inotropism. In contrast to DL-sotalol, D-sotalol is suggested to exert only positive inotropic effects, which were never tested in isolated human myocardium.
  
  
  RESULTS
  Therefore, we investigated the effects of racemic DL-sotalol and its enantiomer D-sotalol in human right atrial muscle strip preparations and in left ventricular muscle strip preparations from nonfailing and end-stage failing human hearts. DL-sotalol and D-sotalol significantly (P < .01) increased peak developed force in atrial preparations by 14.0 +/- 3.4% and 16.7 +/- 3.8%, respectively, but had no effect in ventricular myocardium. In nonfailing ventricular myocardium, both DL-sotalol and D-sotalol shifted the dose-response curve for isoproterenol to higher concentrations (P < .01); however, DL-sotalol was 100-fold more effective than D-sotalol. In non-failing myocardium, a positive force-frequency relation was found between 30 and 120 beats per minute, but isoproterenol was much more powerful in its inotropic effects. In failing myocardium, reduction in stimulation rate from 120 to 30 beats per minute increased peak developed force more pronounced than did the application of isoproterenol.
  
  
  CONCLUSIONS
  (1) D-Sotalol has no relevant beta-adrenoceptor-blocking activity compared with DL-sotalol. (2) Neither DL-sotalol nor D-sotalol exhibit positive inotropic effects in human left ventricular myocardium. (3) Heart rate reduction increases contractile force in end-stage failing human myocardium due to an inverse force-frequency relation and thereby counteracts the potential negative inotropic properties of beta-blockade.
authors.affiliation: Department of Cardiology and Angiology, University of Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Holubarsch
authors.forename: R
authors.initials: R
authors.lastname: Schneider
authors.forename: B
authors.initials: B
authors.lastname: Pieske
authors.forename: T
authors.initials: T
authors.lastname: Ruf
authors.forename: G
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: G
authors.initials: G
authors.lastname: Fraedrich
authors.forename: H
authors.initials: H
authors.lastname: Posival
authors.forename: H
authors.initials: H
authors.lastname: Just
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D011433:Propranolol / Q000494:pharmacology; D013015:Sotalol / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013268:Stimulation, Chemical
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D011433:Propranolol; D013015:Sotalol; D007545:Isoproterenol