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 5␣-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 17␤-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 (155Ϯ7.4 ms, nϭ32) than control females (178Ϯ6.7 ms, nϭ29; PϽ0.05) at cycle lengthϭ1000 ms. The increase in APD 90 induced by 10 Ϫ8 mol/L dofetilide at cycle lengthϭ1000 ms was significantly less in DHT-treated females than normal females (⌬APD 90 ϭ8Ϯ7 and 29Ϯ5 ms, respectively, PϽ0.05). At 10 Ϫ6 mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (PϽ0.05). 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 17␤-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. Key Words: arrhythmia Ⅲ sex Ⅲ dofetilide Ⅲ hormones D rugs that prolong the QT interval induce a greater incidence of arrhythmias (ie, torsades de pointes [TdP]) in women than in men. [1][2][3] The greater propensity to druginduced TdP in females is generally associated with a sex-related difference in ventricular repolarization in the heart such that the rate-corrected QT interval is longer in females than males. 4 -6 Recent clinical and experimental studies propose that gonadal steroids may modulate the sex-related differences in QT interval and propensity toward drug-induced TdP. [7][8][9][10] Bidoggia et al 7 showed that women with virilization exhibit a shorter and faster repolarization time than normal women and castrated men, suggesting that testosterone is an important modulator of ventricular repolarization. In addition, Rodriguez et al 9 demonstrated that women are at greater risk of drug-induced QT prolongation during menstruation and the ovulatory phase of the menstrual cycle, with decreased risk during the luteal phase.Given that progesterone levels are higher during the luteal than the ovulatory and menstruation phases, Rodriguez et al suggest that androgen ...

Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

“…They also showed in female rabbits that testosterone diminishes the proarrhythmic effects of dofetilide. 13 Taken together, these data suggest that testosterone is an important regulator of sex-related differences in ventricular repolarization and the propensity to arrhythmias. However, the mechanisms that underlie the effects of testosterone on ventricular repolarization remain unknown.…”

QSAR Model for Androgen Receptor Antagonism - Data from CHO Cell Reporter Gene Assays

“…• Possible AR antagonism according to the literature [11][12][13][14][15][16][17][18][19][20][21] • Part of a drug group • The presence of a biophore • The presence of an unknown fragment • Overall a distribution between positive and negative corresponding to about 25% and 75%, respectively; two times the presence of positives previously found for the EINECS chemicals [4,5]. 100 drugs were selected due to these criteria.…”

“…Secondary anti-androgenic effect is found for the diureticum spironolactone and probably also for the antiarrhytmics quinidine, procainamide, disopyramide, sotalol, amiodarone, ibutilide and dofitilide [4,7,8,[11][12][13][14][15]. Several epidemiological studies have related statins to improvement of prostate cancer treatment [16][17][18][19].…”

Sex differences and sex hormone effects in long-QT syndrome: what can we learn from rabbit models?

“…Exposing castrated rabbits to testosterone shortens QT duration and reduces drug-induced QT prolongation and EADs [18,28], suggesting that sex hormones-and not only the genetic sex-account for sex differences in cardiac repolarization.…”