Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current.
OBJECTIVE
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), 5 alpha-dihydroxytestosterone (DHT), or 17 beta-estradiol (EST). Four to five weeks later, epicardial and endocardial myocytes were isolated from the left ventricle. Patch clamp technique was performed to assess I(Ca,L).


RESULTS
I(Ca,L) 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,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 I(Ca,L) 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.
Pham
Thai V
TV
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 West 168 St., PH7 West-321, New York, NY 10032, USA.
Robinson
Richard B
RB
Danilo
Peter
P
Rosen
Michael R
MR
D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004699:Endocardium / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009919:Orchiectomy; D010052:Ovariectomy; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000378:metabolism; D011817:Rabbits; D012723:Sex
D020746:Calcium Channels, L-Type; D012739:Gonadal Steroid Hormones; D013196:Dihydrotestosterone; D004958:Estradiol