title: Epiandrosterone, a metabolite of testosterone precursor, blocks L-type calcium channels of ventricular myocytes and inhibits myocardial contractility.
abstract: 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 microM) 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 microM 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 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 n M-100 microM) and reversibly inhibit L-type channel currents carried by Ba2+ (IBa) (IC50=42+/-6 microM) by as much as 50%. At 30 microM, 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.
authors.affiliation: Department of Physiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8412, Japan. sachin_gupte@yahoo.com
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tateyama
authors.forename: Takao
authors.initials: T
authors.lastname: Okada
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Rikuo
authors.initials: R
authors.lastname: Ochi
mesh_terms: D000738:Androsterone / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000378:metabolism; D000860:Hypoxia; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013739:Testosterone / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009573:Nitrites; D013739:Testosterone; D003687:Dehydroepiandrosterone; D009249:NADP; D000738:Androsterone; D002118:Calcium