title: Long-term estradiol replacement decreases contractility of guinea pig coronary arteries to the thromboxane mimetic U46619.
abstract: BACKGROUND
  Estradiol replacement therapy reduces the incidence of coronary artery disease. Current evidence suggests that estradiol may stimulate the production of endothelium-derived NO and thereby reduce the contractile response of vascular smooth muscle. We investigated the effect of long-term replacement of estradiol on NO release and its effect on coronary artery contractility.
  
  
  RESULTS
  Female guinea pigs were ovariectomized and allowed to recover for 100 days. Pellets containing 17 beta-estradiol (0.25, 0.5, 1.5, and 7.5 mg released over 21 days) were placed subcutaneously for 19 to 20 days. Animals were then anesthetized, and the coronary arteries were excised and cut into ring segments. Rings were placed in small-vessel myographs for measurement of isometric force. Contractile responses of coronary arteries to cumulative addition of U46619 (10(-10) to 10(-5) mol/L), a thromboxane mimetic, were measured in the presence and absence of nitro-L-arginine (LNA), a selective NO synthase inhibitor, and methylene blue, a guanylate cyclase inhibitor. Low (0.25-mg) but not high (0.5-, 1.5-, or 7.5-mg) doses of estradiol inhibited the maximal contractile responses to U46619 compared with arteries from untreated castrated animals. In addition, both LNA and methylene blue potentiated contractile responses to U46619 of arteries from animals receiving 0.25 and 0.5 mg but not 1.5 and 7.5 mg estradiol. Negative log EC50 values were significantly inhibited at 0.25 and 7.5 mg but unaffected at 0.5 and 1.5 mg estradiol compared with castrated animals.
  
  
  CONCLUSIONS
  Estradiol at low doses may protect against vasospasm by stimulating endothelium-derived NO release and inhibiting coronary artery contractility.
authors.affiliation: Department of Obstetrics and Gynecology, University of Iowa, Iowa City, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Thompson
authors.forename: C P
authors.initials: CP
authors.lastname: Weiner
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D008751:Methylene Blue / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D004958:Estradiol; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D008751:Methylene Blue