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 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 II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced 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 II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.
Institute of Pharmacological Sciences, University of Milan (Italy).
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Sironi
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Calvio
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Arnaboldi
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Corsini
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Parolari
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de Gasparo
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Tremoli
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Mussoni
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002478:Cells, Cultured; D005342:Fibrinolysis; D006801:Humans; D008323:Mammary Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014469:Umbilical Arteries / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D010959:Tissue Plasminogen Activator; D014633:Valine