Dehydroepiandrosterone (DHEA) Inhibits ICa,L and Window Current by Voltage-Dependent and Independent Mechanisms in Arterial Smooth Muscle Cells
Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone, which has the highest serum concentration among steroid hormones with dehydroepiandrosterone sulfate (DHEAS). DHEA possesses inhibitory action on glucose-6-phosphate dehydrogenase (G6PD), the first pentose-phosphate pathway (PPP) enzyme that reduces NADP(+) to NADPH. DHEA induced relaxation of high K(+)-induced contraction in rat arterial strips, while DHEAS barely induced it. We studied the effects of DHEA on L-type Ca(2+) current (ICa,L) of A7r5 arterial smooth muscle cells (ASMCs) and compared the mechanism of inhibition with that produced by 6-aminonicotinamide (6-AN) competitive inhibitor of G6PD. DHEA moderately inhibited the ICa,L that was elicited from the holding potential (HP) of -80 mV (voltage-independent inhibition, VIDI) and accelerated decay of ICa,L during the depolarization pulse (voltage-dependent inhibition, VDI). DHEA-induced VDI decreased ICa,Lpeak at the depolarized HPs. By applying repetitive depolarization pulses from multiple HPs, novel HP-dependent steady-state inactivation curves (finfinity -HP) were constructed. DHEA shifted finfinity -HP to the left and inhibited the window current (IWD), which was recorded at depolarized HPs and obtained as product of I-V and finfinity -HP. IC50 of inhibition was much higher than serum concentration. DHEA-induced VDI was down-regulated by the dialysis of GDP-beta-S, which shifted finfinity -V to the right prior to the application of DHEA. 6-AN gradually and irreversibly inhibited ICa,L by VIDI, suggesting that the inhibition of G6PD is involved in DHEA-induced VIDI. In 6-AN-pretreated cells, DHEA induced additional inhibition by increasing VIDI and generating VDI. The inhibition of G6PD underlies DHEA-induced VIDI, and DHEA additionally induces VDI as described for Ca(2+) channel blockers.
Ochi, R., Chettimada, S., Kizub, I., & Gupte, S. (2018). Dehydroepiandrosterone (DHEA) Inhibits ICa,L and Window Current by Voltage-Dependent and Independent Mechanisms in Arterial Smooth Muscle Cells. American Journal of Physiology.Heart and Circulatory Physiology, 315 (6), H1602-H1613. https://doi.org/10.1152/ajpheart.00291.2018