Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current

Objectives: Repolarization-prolonging drugs induce torsades de pointes (TdP) in females more than males. The action potential plateau and the early afterdepolarizations that induce TdP are determined, in part, by L-type calcium current (I-Ca.L). Therefore, we studied gender- and hormone-related differences in I-Ca.L in age-, and weight-matched normal male, female and hormonally-treated, castrated rabbits. Methods: Oophorectomized (OVX) or orchiectomized (ORCH) 50- to 60-day-old rabbits were subcutaneously implanted with pellets impregnated with placebo (PLA), 5alpha-dihydroxytestosterone (DHT), or 17beta-estradiol (EST). Four to five weeks later, epicardial and endocardial myocytes were isolated from the left ventricle. Patch clamp technique was performed to assess Results: density (measured as peak current density [pA/pF] at + 15 mV, V-h = -40 mV), was greater in female epicardium (-7.4 +/- 0.9) than endocardium (-5.6 +/- 0.7, P < 0.05), while male epicardial I-Ca.L density (-6.5 ± 0.7) did not differ from endocardial (-5.9 ± 1.0, P > 0.05). OVX-female, DHT and EST-treated groups had epicardial I-Ca,I-L density (-5.6 +/- 0.6, and -5.9 +/- 0.7, respectively) greater than endocardial (-4.3 +/- 0.3, and -3.6 +/- 0.4, P < 0.05). However, OVX-females had hormone levels not significantly different from female controls and EST-treated females had non-physiological levels of estradiol. There were no differences between endocardial and epicardial I-Ca.L activation and inactivation. In contrast, epicardial-endocardial differences in I-Ca.L density in EST-treated OVX-females were associated with epicardial-endocardial differences in I-Ca.L activation and conductance in DHT-treated OVX-females only epicardial-endocardial activation differed. The other groups, showed no I-Ca.L transmural gradient, or differences in activation, inactivation or conductance. Conclusions: The greater dispersion in I-Ca.L density of OVX-DHT and OVX-EST than OVX-PLA suggests both hormones can modulate I-Ca.L density in females. That gonadal steroids had no effect on 1,., dispersion in males suggests gender differences in mechanism of action of both hormones. The greater I-Ca.L dispersion in females may contribute to gender differences in repolarization. (C) 2002 Elsevier Science B.V. All rights reserved.