title: Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys.
abstract: Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.
authors.affiliation: Dimera, Inc., 2525 NW Lovejoy, Suite 311, Portland, Oregon 97210, USA.
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Mishra
authors.forename: R Kent
authors.initials: RK
authors.lastname: Hermsmeyer
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Philip
authors.initials: P
authors.lastname: Sarrel
authors.forename: Barry
authors.initials: B
authors.lastname: Uchida
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Burry
authors.forename: D Roger
authors.initials: DR
authors.lastname: Illingworth
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Nordt
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*
chemical_list: D013196:Dihydrotestosterone; D017258:Medroxyprogesterone Acetate