Epiandrosterone, a metabolite of testosterone precursor, blocks L-type calcium channels of ventricular myocytes and inhibits myocardial contractility

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 muM) also dose-dependently decreases left-ventricular developed pressure (LVDP), the rate of myocardial contraction (+dp/dt), and the pressure rate product (PRP); at 100 muM EPI, LVDP (131 +/- 9 vs 34 +/- 7 mmHg), +dp/dt (1515 +/- 94 vs 542 +/- 185 mmHg/s). and PRP (37870 +/- 2471 vs 9498 +/- 2375 HR x 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 nM-100 muM) and reversibly inhibit L-type channel currents carried by Ba2+ (1(Ba)) (IC50 = 42 +/- 6 muM) by as much as 50%. At 30 muM, EPI shifted the steady-state inactivation curve to more negative potentials (V-50 =-26.6 mV vs -38.0 mV), thereby accelerating the decay of 1(Ba) 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. (C) 2002 Elsevier Science Ltd. All rights reserved.