Dihydrotestosterone Pretreatment Diminishes the Severity of Drug-Induced Torsades de Pointes.

Abstract

Testosterone and dihydrotestosterone (DHT) attenuate drug-induced lengthening of ventricular repolarization, but it is unknown whether they influence drug-induced torsades de pointes (TdP). We tested the hypothesis that DHT reduces the incidence and severity of drug-induced TdP. Male New Zealand white rabbits underwent orchiectomy and were implanted with two subcutaneous sustained-release pellets containing DHT 50 mg (100 mg, n=23) or placebo (n=20). After 7 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Dofetilide 100 nM was perfused for 30 minutes. Median (Q1, Q3) serum DHT concentrations were higher in DHT-treated rabbits [314.0 (232.5, 388.6) versus 32.5 (28.5, 36.2) ng/dL, p<0.0001]. The incidence of TdP in the DHT and placebo groups was 6/23 (26%) versus 8/20 (40%), respectively (p=0.33). In hearts that developed TdP, the median (Q1, Q3) number of episodes was lower in the DHT group [2 (2, 3.5) versus 18.5 (12.5, 20.5), p=0.01]. The median time to first TdP episode was longer [18.5 (17.3, 21.3) versus 10.5 (12.5, 20.5) minutes, p=0.01] and the TdP burden (median total number of TdP beats per heart) was lower in the DHT group [11.5 (9.5-46.5) versus 271 (99.3-440.3) beats, p=0.007]. Pre-dofetilide Fridericia-corrected QT (QTF) intervals were shorter in the DHT group [377 (366, 390) vs 385 (378, 401) ms, p=0.02]. Maximum QTF interval during dofetilide perfusion was shorter in the DHT group [399 (390, 410) vs 414 (399, 442) ms, p=0.007]. In conclusion, DHT diminishes the severity of dofetilide-induced TdP.