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.

Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity

“…RM were subjected to the coronary artery combined vasoconstrictor stimulus in a catheterization laboratory protocol described previously (16,17,26,28,29,31). Briefly, the stepwise injection protocol tests the ability of slow (1 ml over 30 s) intracoronary infusion of vasoactive endogenous substances, 100 M serotonin (S) and 1 M U-46619 (U, a thromboxane analog), to initiate the prolonged (Ͼ5 min), severe (to Ͻ33% of control diameter) vasoconstriction that defines CH producing ischemia and, if unrelieved, myocardial infarction.…”

“…Acetylcholine-induced vasodilation of 5-8% was found in all E 3-treated RM, indicating normal endothelial dilator function. An observer blinded to the treatment groups measured coronary artery diameters (⌽) from serial angiograms to define the points of minimum ⌽ after each injection (16,17,26,28,29,31). The corresponding anatomic point on the control image was the 100% reference ⌽.…”

“…Average minimum ⌽ of major epicardial coronary arteries were digitally analyzed to determine minimum ⌽. A reduction in ⌽ to Ͻ33% of control for Ͼ5 min was classified as CH, whether or not focal vasospasm was observed (16,17,26,28,29,31).…”

“…Coronary VMC used in cell culture live cell fluorescent, immunocytochemistry, and Western blot studies were obtained from a separate group of 12 Ovx RM through the tissue distribution program at the Oregon National Primate Research Center. Coronary VMC culture protocols were performed as described previously (27)(28)(29). VMC Ca 2ϩ responses to 15 s of S ϩ U pulse stimulation were determined as described previously (17,(27)(28)(29) after Ͼ72 h of in vitro exposure to ER-␤ ligand (or placebo).…”

“…Coronary VMC culture protocols were performed as described previously (27)(28)(29). VMC Ca 2ϩ responses to 15 s of S ϩ U pulse stimulation were determined as described previously (17,(27)(28)(29) after Ͼ72 h of in vitro exposure to ER-␤ ligand (or placebo). When selective ER-␤ antagonist treatment (e.g., R,R-THC) was also performed, the antagonist was added to VMC culture plates 3 h before subsequent treatment with the agonist (and continued during the entire agonist treatment).…”