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 incidences of drug-induced torsade de pointes in women than in men are incompletely defined, although gonadal steroids are assumed to be important determinants of these differences.


RESULTS
We used microelectrode techniques to study isolated rabbit right ventricular endocardium from control male and female and castrated male (ORCH) and female (OVX) rabbits. Action potential duration to 30% repolarization (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 prolonged APD in female and ORCH more than in male and OVX. At 10(-)(6) mol/L dofetilide (cycle length=1 second), the incidence of early afterdepolarizations was: female, 67%; ORCH, 56%; male, 40%; and OVX, 28%. Serum 17beta-estradiol levels were unrelated to the effects of dofetilide, but as testosterone levels increased, the dofetilide effect to increase APD diminished, as did 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 this model, drugs that block I(Kr) but not I(Ks) prolong repolarization in a way that suggests that protection from excess prolongation in males is attributable to testosterone, whereas the risk of excess prolongation of repolarization in females is related to sex-determined factors in addition to estrogen.
Pham
T V
TV
Department of Pharmacology, Center for Molecular Therapeutics, The Partnership for Women's Health, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
Sosunov
E A
EA
Gainullin
R Z
RZ
Danilo
P
P
Rosen
M R
MR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002369:Castration; D027682:Cation Transport Proteins; D002839:Chromans / Q000633:toxicity; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004699:Endocardium / Q000187:drug effects* / Q000503:physiopathology; D004958:Estradiol / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D007529:Isoflavones / Q000494:pharmacology; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D010496:Pericardium / Q000187:drug effects* / Q000503:physiopathology; D010627:Phenethylamines / Q000633:toxicity; D048789:Phytoestrogens; D028321:Plant Preparations / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000633:toxicity*; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011817:Rabbits; D012737:Sex Factors; D013449:Sulfonamides / Q000633:toxicity
D027682:Cation Transport Proteins; D002839:Chromans; D051638:Ether-A-Go-Go Potassium Channels; D007529:Isoflavones; C092509:KCNH6 protein, human; D010627:Phenethylamines; D048789:Phytoestrogens; D028321:Plant Preparations; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk); D013196:Dihydrotestosterone; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D004958:Estradiol; C063533:dofetilide