on March 18, 2004
Published online before print March 18, 2004, doi: 10.1161/01.ATV.0000126372.14332.70
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Submitted on December 11, 2003
Accepted on March 5, 2004
Prevention of Coronary Hyperreactivity in Preatherogenic Menopausal Rhesus Monkeys by Transdermal Progesterone
R. Kent Hermsmeyer *;
From the Dimera Incorporated (R.K.H., R.G.M.) and Oregon Health and Science University (D.P., B.U., M.K.A., K.A.B., D.R.I.), Portland, Ore; University of Southern California (F.Z.S.), Los Angeles, Calif; St. George’s Hospital Medical School (J.C.K.), London, UK; and Rhein Consulting Laboratories (F.J.N.), Portland, Ore.
* To whom correspondence should be addressed. E-mail: rgm{at}dimera.net.
Objective--To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys.
Methods and Results--Ovariectomized rhesus monkeys fed an atherogenic diet (AD) for 19 months were treated with an investigational transdermal P cream (n=7) or identical placebo cream (n=5) for 4 weeks. Aorta and carotids showed fatty streaks and Oil Red O staining demonstrated lipid deposition. Serum P levels in P-treated rhesus monkeys (0.6 ng/mL) were significantly greater than placebo (0.2 ng/mL). Significant elevation of cholesterol, LDL cholesterol, and HDL cholesterol, was noted in all animals. Lp(a) was significantly attenuated in the AD-fed P-treated monkeys. Coronary angiographic experiments stimulating vasoconstriction by intracoronary injections of serotonin plus U46619 showed exaggerated prolonged actions amplified by AD, but significant protection against severe prolonged vasoconstriction in P-treated monkeys. Immunocytochemistry confirmed co-expression of P and thromboxane prostanoid (TP) receptors in coronaries and aorta. Western blotting demonstrated TP receptor attenuation in vascular muscle after P treatment.
Conclusions--Coronary hyperreactivity, a putative component of coronary artery disease mediated via increased vascular muscle thromboxane prostanoid receptors, can be prevented by subphysiological levels of P, not only in nonatherosclerotic (previously shown) but also in preatherosclerotic primates.
Key words: coronary occlusion • menopause • progesterone replacement • cardiac catheterization
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