Epiandrosterone, a Metabolite of Testosterone Precursor, Blocks L-type Calcium Channels of Ventricular Myocytes and Inhibits Myocardial Contractility

S. A. Gupte, M. Tateyama, T. Okada, M. Oka and R. Ochi. Epiandrosterone, a Metabolite of Testosterone Precursor, Blocks L-type Calcium Channels of Ventricular Myocytes and Inhibits Myocardial Contractility. Journal of Molecular and Cellular Cardiology (2002) 34, 679–688. The dehydroepiandrosterone metabolite epiandrosterone (EPI) inhibits the pentose phosphate pathway (PPP) and dilates isolated blood vessels pre-contracted by partial depolarization. We found that EPI (10–100 μM) also dose-dependently decreases left-ventricular developed pressure (LVDP), the rate of myocardial contraction (+d p /d t), and the pressure rate product (PRP); at 100 μimage EPI, LVDP (131±9 vs 34±7 mmHg), +d p /dt (1515±94 vs 542±185 mmHg/s), and PRP (37870±2471 vs 9498±2375 HR×mmHg/min) were all significantly (P<0.05) reduced. EPI also elevated CPP in isolated hearts, decreased levels of myocardial NADPH and nitrite, and dose-dependently relaxed rat aortic rings pre-contracted with KCl. Electrophysiological analysis of single ventricular myocytes using whole cell clamp showed EPI to dose-dependently (100 n M–100 μM) and reversibly inhibit L-type channel currents carried by Ba2+ (IBa) (IC50=42±6 μM) by as much as 50%. At 30 μM, EPI shifted the steady-state inactivation curve to more negative potentials (V50=−26.6 mV vs −38.0 mV), thereby accelerating the decay of IBa during depolarization. These results suggest that EPI may act as a L-type Ca2+ channel antagonist with properties similar to those of 1,4-dihydropyridine (DHP) Ca2+ channel blockers.