Antithrombin III prevents renal dysfunction and hypertension induced by enhanced intravascular coagulation in pregnant rats: pharmacological confirmation of the benefits of treatment with antithrombin III in preeclampsia.
We tested the hypothesis that enhanced intravascular coagulation in pregnancy could produce clinical symptoms similar to those of preeclampsia, such as hypertension, proteinuria, and edema. Having confirmed this, we then examined whether the pathological changes caused by intravascular coagulation could be suppressed by administration of antithrombin III (AT III), an endogenous inhibitor active to thrombin and factor X a. Intravascular coagulation was induced in Wistar rats on day 16-20 of pregnancy by 1-h arterial infusion of tissue thromboplastin (TP) through the left ventricle of the heart. One hour after the end of the infusion period, organ blood flows were measured by the radioactive ((57)Co-labeled) microsphere method, and fibrin deposition in organs was measured by radiolabeling with [(125)I] fibrinogen injected before TP infusion. Infusion of TP produced fibrin deposition in the kidney, lung, and liver, but not in the myometrium and placenta, as well as an 80% decrease in renal blood flow (RBF), with oliguria and proteinuria. TP also caused an increase in blood pressure (BP) accompanied by an increase in plasma renin activity (PRA), both of which were suppressed by bilateral nephrectomy before TP infusion. The prophylactic administration of AT III concentrates (60 or 300 U/kg intravenously (i.v.), followed by infusion of 30 or 150 U/kg/2 h, respectively) prevented all pathological changes in a dose-dependent manner. AT III increased placental blood flow regardless of the state of coagulation. These findings suggest that intravascular coagulation plays a significant part in the pathophysiology of preeclampsia and that AT III concentrates may have therapeutic potential in the treatment of this condition.
Shinyama
H
H
Pharmacology Laboratories, Research Division, The Green Cross Corporation, Osaka, Japan.
Akira
T
T
Uchida
T
T
Hirahara
K
K
Watanabe
M
M
Kagitani
Y
Y
D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006973:Hypertension / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011225:Pre-Eclampsia / Q000188:drug therapy*; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000517:prevention & control*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000097:blood; D012709:Serum Albumin / Q000378:metabolism; D013925:Thromboplastin / Q000494:pharmacology
D012709:Serum Albumin; D000990:Antithrombin III; D005337:Fibrin; D013925:Thromboplastin; D012083:Renin