Effects of dofetilide on electrical dispersion and arrhythmias in post-infarcted anesthetized dogs.
An increase in dispersion of myocardial refractoriness has been shown to coincide with a greater risk of inducible ventricular arrhythmias. We compared the dispersion of electrophysiologic parameters and antiarrhythmic effects of dofetilide (0.03, 0.1, 0.3 and 1 mg/kg i.v.) in post-infarcted anesthetized dogs. Animals were tested for inducibility of arrhythmias using a programmed electrical stimulation (PES) protocol, and divided into inducible (I) and non-inducible (NI) groups. In addition, myocardial vulnerability was measured using ventricular fibrillation thresholds (VFT), as well as susceptibility to sudden cardiac death (SCD). Dofetilide significantly increased ventricular effective refractory periods (ERP) and monophasic action potential durations (APD) in a dose-dependent manner. The standard deviation of ERP, which was used as an index of dispersion of refractoriness, increased from sham (control value of 5.4 +/- sd 2.5 ms), non-inducible (control value of 11.0 +/- 5.5 and 8.0 +/- 3.7 ms for vehicle and dofetilide groups, respectively) and inducible states (control value of 17.3 +/- 6.2 and 21.6 +/- 7.1 ms for vehicle and dofetilide groups, respectively). However, dofetilide treatment did not alter dispersion of refractoriness over the dose range studied. Dofetilide did not significantly increase inducibility in the NI group (2 out of 8 [25%] compared to 0 out of 9 [0%] in vehicle treated animals). In the I group, dofetilide (0.3 mg/kg) treated animals converted 2 out of 7 (29%) to NI, and 5 out of 7 (71%; significant at p < 0.05) to a NI or non sustained ventricular tachycardia. There were no significant changes in VFT following the last dose of dofetilide given. Dofetilide did not significantly affect SCD survival (88% and 29% in the NI and I group, respectively) relative to vehicle (66% and 50% in the NI and I group, respectively). Although infarct sizes were significantly greater in the I groups, there was no difference between vehicle and dofetilide animals within these groups. In conclusion, dofetilide increased ERP and APD values, but did not affect dispersion of refractoriness. Thus, changes in dispersion of refractoriness may be used as a marker for inducibility in untreated animals, but it did not predict the antiarrhythmic effects observed with dofetilide.
D'Alonzo
A J
AJ
Bristol-Myers Squibb Pharmaceutical Research Institute Department of Pharmacology, Princeton, New Jersey 08543-4000, USA.
Sewter
J C
JC
Darbenzio
R B
RB
Hess
T A
TA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D003645:Death, Sudden / Q000209:etiology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D010627:Phenethylamines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide