Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which sugges ts that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a rec ently developed angiotensin II antagonist that is highly specific: and sele ctive for the angiotensin II subtype 1 receptor, on plasminogen activator i nhibitor-1 secretion by smooth muscle cells isolated from rat and human ves sels. Angiotensin II induced a time- and concentration-dependent increase o f plasminogen activator inhibitor activity in supernatants of rat aortic ce lls, which reached a plateau after 6 hours of incubation with 100 nmol/L an giotensin II (2.4 +/- 0.6-fold over control value; P<0.001). The angiotensi n II-induced plasminogen activator inhibitor activity was inhibited, in a c oncentration-dependent manner, by valsartan with an IC,, value of 21 nmol/L . Valsartan fully prevented the angiotensin IT-induced increase in plasmino gen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II dou bled the secretion of plasminogen activator inhibitor-1 by smooth muscle ce lls obtained from human umbilical and internal mammary arteries, and valsar tan fully prevented it. Angiotensin II did not affect the secretion of tiss ue plasminogen activator antigen by any of the cell systems tested. Thus, v alsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activato r in arterial rat and human smooth muscle cells.