Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits

Abstract

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 5α-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization. Methods and 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 17β-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 (APD 90 ) 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 APD 90 induced by 10 −8 mol/L dofetilide at cycle length=1000 ms was significantly less in DHT-treated females than normal females (ΔAPD 90 =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 17β-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.