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Medroxyprogesterone Acetate and Dihydrotestosterone Induce Coronary Hyperreactivity in Intact Male Rhesus Monkeys

Dimera, Inc. (R.G.M., R.K.H.), Portland, Oregon 97210; Oregon Health and Science University (B.U., K.A.B., D.R.I.), Portland, Oregon 97239; Nagoya City Kohsein Hospital (K.M.), Nagoya, Japan; Yale University Medical School (P.S.), New Haven, Connecticut 06510; University of Southern California (F.Z.S.), Los Angeles, California 90033; and Rhein Consulting Laboratories (F.J.N.), Portland, Oregon 97225

Address all correspondence and requests for reprints to: Dr. R. Kent Hermsmeyer, Dimera, Inc., 2525 NW Lovejoy, Suite 311, Portland, Oregon 97210. E-mail: rkh{at}dimera.net.

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 A₂ 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.

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