Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits.
BACKGROUND
Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5alpha-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization.


RESULTS
We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17beta-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD90) was significantly shorter in DHT-treated (155+/-7.4 ms, n=32) than control females (178+/-6.7 ms, n=29; P<0.05) at cycle length=1000 ms. The increase in APD90 induced by 10(-8) mol/L dofetilide at cycle length=1000 ms was significantly less in DHT-treated females than normal females (DeltaAPD90=8+/-7 and 29+/-5 ms, respectively, P<0.05). At 10(-6) mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (P<0.05).


CONCLUSIONS
Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17beta-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia.
Pham
Thai V
TV
Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Fla, USA.
Sosunov
Eugene A
EA
Anyukhovsky
Evgeny P
EP
Danilo
Peter
P
Rosen
Michael R
MR
D000200:Action Potentials / Q000187:drug effects; D000222:Adaptation, Physiological; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D046508:Culture Techniques; D013196:Dihydrotestosterone / Q000097:blood / Q000494:pharmacology*; D004553:Electric Conductivity; D004699:Endocardium / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects*; D007700:Kinetics; D010627:Phenethylamines / Q000037:antagonists & inhibitors*; D026902:Potassium Channel Blockers / Q000037:antagonists & inhibitors*; D011817:Rabbits; D013449:Sulfonamides / Q000037:antagonists & inhibitors*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D013196:Dihydrotestosterone; D004958:Estradiol; C063533:dofetilide