(Hypertension. 2001;37:961.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
From the Institute of Pharmacological Sciences (L.S., A.M.C., L.A., A.C., E.T., L.M.) and the Department of Cardiac Surgery (A.P.), University of Milan (Italy), and the Pharmaceutical Division, Novartis, Basel, Switzerland (M. de G.).
Correspondence to Elena Tremoli, Laboratory of Pharmacology of Thrombosis and Atherosclerosis, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail Elena.Tremoli{at}unimi.it
Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4±0.6-fold over control value; P<0.001). The angiotensin IIinduced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC50 value of 21 nmol/L. Valsartan fully prevented the angiotensin IIinduced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin IIinduced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.
Key Words: plasminogen fibrinolysis angiotensin II receptors, angiotensin valsartan muscle, smooth
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