INCREASED EXPRESSION OF THE CARDIAC L-TYPE CALCIUM-CHANNEL IN ESTROGEN RECEPTOR-DEFICIENT MICE

Steroid hormones control the expression of many cellular regulators, a nd a role for estrogen in cardiovascular function and disease has been well documented. To address whether the activity of the L-type Ca2+ c hannel, a critical element in cardiac excitability and contractility, is altered by estrogen and its nuclear receptor, we examined cardiac m yocytes from male mice in which the estrogen receptor gene had been di srupted (ERKO mice). Binding of dihydropyridine Ca2+ channel antagonis t isradipine (PN200-110) was increased 45.6% in cardiac membranes from the ERKO mice compared to controls, suggesting that a lack of estroge n receptors in the heart increased the number of Ca2+ channels. Whole- cell patch clamp of acutely dissociated adult cardiac ventricular myoc ytes indicated that Ca2+ channel current was increased by 49% and acti on potential duration was increased by 75%. Examination of electrocard iogram parameters in ERKO mice showed a 70% increase in the QT interva l without significant changes in PQ or QRS intervals. These results sh ow that the membrane density of the cardiac L-type Ca2+ channel is reg ulated by the estrogen receptor and suggest that decreased estrogen ma y lead to an increase in the number of cardiac L-type Ca2+ channels, a bnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.