Effects of progesterone and estrogen on endothelial dysfunction in porcine coronary arteries.
BACKGROUND
The effects of hormone replacement therapy (HRT) on the vascular endothelium have been controversial. In this study, we determined the effects of HRT on endothelium-dependent relaxation in a porcine coronary artery model.


METHODS
Coronary artery rings harvested from female swine were incubated as controls or with estrogen (10(-9), 10(-8), 10(-7) g/L), progesterone (1 x 10(-6), 1 x 10(-5), 5 x 10(-5) g/L), or a combination of the two (10(-8)g/L estrogen, 1 x 10(-5)g/L progesterone). After 24 h in tissue culture, the rings were tested on a myograph system to measure contraction and endothelium-dependent relaxation. Myograph analysis was performed with the thromboxane A2 analogue U46619 for contraction and bradykinin or sodium nitroprusside for relaxation. Nitric oxide synthase (eNOS) levels were determined by immunohistochemistry. Levels of superoxide anion in the progesterone or estrogen treated tissues were assessed by lucigenin-enhanced chemiluminescence analysis.


RESULTS
In response to 10(-7)M bradykinin, porcine coronary artery rings treated with 1 x 10(-6), 1 x 10(-5) and 5 x 10(-5) g/L of progesterone showed a significant reduction in endothelium-dependent vasorelaxation by 36%, 45%, and 68%, respectively, as compared to controls (P <0.05). However, rings treated with estrogen showed no significant difference as compared to controls. Furthermore, estrogen treatment with progesterone reversed the effect of progesterone, showing no difference in vessel relaxation as compared to controls. There were no differences in endothelium-independent vasorelaxation (sodium nitroprusside) or in smooth muscle contractility (U46619) between the control and the hormone-treated groups. The eNOS immunoreactivity was reduced in progesterone-treated coronary artery rings. Furthermore, coronary endothelium exposed to progesterone showed a 59% increase in superoxide anion production, while estrogen produced a 67% decrease when compared to controls (P <0.05 for both).


CONCLUSIONS
This data suggests that the progesterone component of HRT has a detrimental influence on endothelium-dependent relaxation. This effect appears to be related to decreased eNOS levels, as well as increased consumption of NO by superoxide anion in the endothelium of tissues exposed to progesterone. Estrogen can block progesterone-induced endothelial dysfunction and superoxide anion production in the pig coronary artery model.
Cox
Mitchell W
MW
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and The Methodist Hospital, Houston, Texas 77030, USA.
Fu
Weiping
W
Chai
Hong
H
Paladugu
Ramesh
R
Lin
Peter H
PH
Lumsden
Alan B
AB
Yao
Qizhi
Q
Chen
Changyi
C
D000818:Animals; D001158:Arteries / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D012739:Gonadal Steroid Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine; D014652:Vascular Diseases / Q000188:drug therapy; D014664:Vasodilation / Q000187:drug effects
D012739:Gonadal Steroid Hormones; D009569:Nitric Oxide; D011374:Progesterone; D004958:Estradiol; D019001:Nitric Oxide Synthase