Impact of sex and gonadal steroids on prolongation of ventricular repolarization and arrhythmias induced by I-K-blocking drugs

Background-Mechanisms for longer rate-corrected QT intervals and higher inc idences of drug-induced torsade de pointes in women than in men are incompl etely defined, although gonadal steroids are assumed to be important determ inants of these differences. Methods and Results-We used microelectrode techniques to study isolated rab bit right ventricular endocardium from control male and female and castrate d male (ORCH) and female (OVX) rabbits. Action potential duration to 30% re polarization (APD(30)) was significantly shorter in male than female and in ORCH than OVX at a cycle length of 500 ms. The I-Ks blocker chromanol 293B had no effect on APD in males or females. The I-Kr blocker dofetilide prol onged APD in female and ORCH more than in male and OVX. At 10(-6) mol/L dof etilide (cycle length=1 second), the incidence of early afterdepolarization s was. female, 67%; ORCH, 56%; male, 40%: and OVX, 28%. Serum 17 beta -estr adiol levels were unrelated to the effects of dofetilide, but as testostero ne levels increased, the dofetilide effect to increase APD diminished, as d id early afterdepolarization incidence. Conclusions-Sex-related differences in basal right ventricular endocardial AP configuration persist in castrated rabbits, suggesting that extragonadal factors contribute to the differences in ventricular repolarization, In th is model, drugs that block I-Kr but not I-Ks prolong repolarization in a wa y that suggests that protection from excess prolongation in males is attrib utable to testosterone, whereas the risk of excess prolongation of repolari zation in females is related to sex-determined factors in addition to estro gen.