title: EMD 57033 enhances arrhythmias associated with increased wall-stress in the working rat heart.
abstract: 1. EMD 57033 produces a positive inotropic effect by increasing the sensitivity of cardiac muscle myofilaments to calcium. Since the elevation in intracellular calcium produced by conventional inotropic compounds is thought to be arrhythmogenic, it is hoped that compounds such as EMD 57033 may increase cardiac output without exacerbating arrhythmias in patients with cardiac failure. This is the first study to examine whether EMD 57033 influences the susceptibility of the heart to ventricular arrhythmias. 2. We used the isolated working rat heart to investigate the effect of EMD 57033 on wall-stress-induced ventricular arrhythmia. Arrhythmias were induced by increases in ventricular afterload, and the effect of 2 mumol/l EMD 57033 on ventricular arrhythmias was investigated. The effect of 2 mumol/l EMD 57033 on contractility and arrhythmias was also assessed in the presence of different levels of perfusate calcium. 3. EMD 57033 was positively inotropic in the working rat heart, but it also produced a reversible increase in wall-stress-induced ventricular arrhythmia. The incidence of both ventricular ectopics and complex arrhythmias such as ventricular tachycardia were significantly increased by EMD 57033. Arrhythmias increased progressively as the level of perfusate calcium was raised within the physiological range. 4. The mechanism by which EMD 57033 increases wall-stress-induced arrhythmia is unclear, but it seems unlikely to be directly due to elevation of intracellular calcium. Further studies of the arrhythmogenic profile of this novel compound are required in a variety of models to assess its suitability and safety as a potentially therapeutic compound in heart failure.
authors.affiliation: Department of Physiology, School of Medical Sciences, University of Bristol, U.K.
authors.forename: S J
authors.initials: SJ
authors.lastname: Evans
authors.forename: A J
authors.initials: AJ
authors.lastname: Levi
authors.forename: J A
authors.initials: JA
authors.lastname: Lee
authors.forename: J V
authors.initials: JV
authors.lastname: Jones
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000209:etiology*; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D013829:Thiadiazines / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; D002118:Calcium