Treatment with raloxifene and 17beta-estradiol differentially modulates nitric oxide and prostanoids in venous endothelium and platelets of ovariectomized pigs.
Oral treatment with raloxifene, a synthetic estrogen receptor modulator (SERM), or 17beta-estradiol (E2) increases risk for venous thrombosis in women. Acute application of either substance releases endothelium-derived factors from isolated femoral veins but it is not known how their chronic use affects venous functions or the interaction of platelets with veins. This study tested the hypothesis that treatment of ovariectomized animals with oral raloxifene or E2 would increase release of proaggregatory factors from venous endothelium and platelets. Ovariectomized (OVX) pigs were either untreated or treated with oral raloxifene (60 mg/day) or E2 (2 mg/day) for 4 weeks. Plasma concentrations of nitric oxide were comparable in both treatment groups and greater than in OVX pigs. Ratio of plasma thromboxane to prostacyclin was twofold greater in raloxifene compared to E2-treated pigs. In isolated femoral veins, NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) augmented endothelium-dependent relaxations to adenosine diphosphate in veins from E2-treated pigs but inhibited relaxations in veins from raloxifene-treated pigs. Addition of indomethacin (10(-5) M) reversed these effects. Endothelium-dependent relaxations to thrombin were inhibited by L-NMMA only in OVX and raloxifene-treated pigs. Autologous platelets contracted veins in all groups; the magnitude of contractions depended upon the number of platelets and existing tone. Basal release of thromboxane from platelets was greatest in raloxifene compared to OVX or E2-treated pigs. Raloxifene treatment compared to E2 increased production of contractile and proaggregatory prostanoids from venous endothelium and platelets. These differences, if found in humans, may contribute to varying degrees of thrombotic risk with the SERM compared to the natural hormone.
Lewis
Debra A
DA
Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Avsar
Murat
M
Labreche
Peter
P
Bracamonte
Margarita
M
Jayachandran
Muthuvel
M
Miller
Virginia M
VM
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005268:Femoral Vein / Q000166:cytology*; D009569:Nitric Oxide / Q000378:metabolism*; D010052:Ovariectomy; D011453:Prostaglandins / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D013552:Swine
D011453:Prostaglandins; D009569:Nitric Oxide; D020849:Raloxifene Hydrochloride; D004958:Estradiol