Prevention of coronary hyperreactivity in preatherogenic menopausal rhesus monkeys by transdermal progesterone.
OBJECTIVE
To test if transdermal progesterone (P) confers coronary vascular protection in surgically menopausal preatherosclerotic rhesus monkeys.


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.
Hermsmeyer
R Kent
RK
Dimera Incorporated, Portland, Ore 97210, USA. rkh@dimera.net
Mishra
Rajesh G
RG
Pavcnik
Dusan
D
Uchida
Barry
B
Axthelm
Michael K
MK
Stanczyk
Frank Z
FZ
Burry
Kenneth A
KA
Illingworth
D Roger
DR
Juan
Carlos
C
Nordt
Frank J
FJ
D000279:Administration, Cutaneous; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003327:Coronary Disease / Q000473:pathology / Q000517:prevention & control*; D003329:Coronary Vasospasm / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology*; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D005260:Female; D020249:Hormone Replacement Therapy; D008055:Lipids / Q000032:analysis / Q000097:blood; D017270:Lipoprotein(a) / Q000097:blood; D008253:Macaca mulatta; D008594:Menopause, Premature; D010052:Ovariectomy; D011276:Pregnanediol / Q000652:urine; D011374:Progesterone / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D008055:Lipids; D017270:Lipoprotein(a); D012701:Serotonin; D011374:Progesterone; D011276:Pregnanediol