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

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Abstract
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 (ICa,L). Therefore, we studied gender- and hormone-related differences in ICa,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), 5α-dihydroxytestosterone (DHT), or 17β-estradiol (EST). Four to five weeks later, epicardial and endocardial myocytes were isolated from the left ventricle. Patch clamp technique was performed to assess ICa,L. Results:ICa,L density (measured as peak current density [pA/pF] at +15 mV, Vh=−40 mV), was greater in female epicardium (−7.4±0.9) than endocardium (−5.6±0.7, P0.05). OVX-female, DHT and EST-treated groups had epicardial ICa,L density (−5.6±0.6, and −5.9±0.7, respectively) greater than endocardial (−4.3±0.3, and −3.6±0.4, PICa,L activation and inactivation. In contrast, epicardial–endocardial differences in ICa,L density in EST-treated OVX-females were associated with epicardial–endocardial differences in ICa,L activation and conductance; in DHT-treated OVX-females only epicardial–endocardial activation differed. The other groups, showed no ICa,L transmural gradient, or differences in activation, inactivation or conductance. Conclusions: The greater dispersion in ICa,L density of OVX–DHT and OVX–EST than OVX–PLA suggests both hormones can modulate ICa,L density in females. That gonadal steroids had no effect on ICa,L dispersion in males suggests gender differences in mechanism of action of both hormones. The greater ICa,L dispersion in females may contribute to gender differences in repolarization.

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