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DOI: 10.1055/s-0037-1615041
Nitric Oxide and Prostacyclin Are Involved in Antithrombotic Action of Captopril in Venous Thrombosis in Rats
Publication History
Received
02 November 1996
Accepted after resubmission
03 February 1998
Publication Date:
07 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199806/lookinside/thumbnails/10-1055-s-0037-1615041-1.jpg)
Summary
The long-term administration of captopril to patients with a left ventricular dysfunction after myocardial infarction reduces the rate of recurrent coronary thrombosis. Thus, in the present study we investigated the influence of angiotensin-converting enzyme inhibitors (ACE-Is) on experimental venous thrombosis in normotensive rats and the involvement of NO and PGI2 in this effect. Animals were treated with captopril (1.5, 5 or 25 mg/kg twice daily, CAP), enalapril (15 mg/kg once daily, ENA) or distilled water for 10 days, per os. After ligation of the vena cava the thrombus weight decreased in both CAP and ENA treated rats. The effect was most pronounced in animals given the highest dose of CAP (p<0.0001 vs. control) and was significantly stronger than observed in ENA treated animals (CAP vs. ENA p<0.01). The mean blood pressure measured by the “tail cuff” method and platelet aggregation were not altered by either of the ACE-Is. The antithrombotic activity of CAP was reduced by indomethacin (2.5 mg/kg, s.c.) and independently by the NO-synthase inhibitor NG-nitro L-arginine methyl ester (3 mg/kg i.v. bolus + 3 mg/kg/h i.v. infusion, L-NAME). In the latter case CAP regained its antithrombotic properties in rats pretreated with L-Arginine (300 mg/kg i.v. + 300 mg/kg/h i.v.) before administration of L-NAME (p<0.05 vs. control). Moreover, the concomitant administration of indomethacin and L-NAME failed to completely abolish the antithrombotic action of captopril. Similar effects were observed in respect to the incidence of venous thrombosis. Our study documents a novel and important effect of ACE-Is on the vein thrombotic process and demonstrates the involvement of NO and PGI2 in this phenomenon.
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References
- 1 Ertl G, Kloner RA, Alexander RW, Braunwald E. Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 1982; 65: 40-8.
- 2 Linz W, Schölkens BA, Han Y-F. Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts. J Cardiovasc Pharmacol 1986; 8 (Suppl. 010) S91-S9.
- 3 Liu Y-H, Yang X-P, Sharov VG, Sigmon DH, Sabbah HN, Carretero OA. Paracrine systems in the cardioprotective effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury in rats. Hypertension 1996; 27: 7-13.
- 4 Pfeffer MA, Braunwald E, Moýe LA, Basta L, Brown Jr EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau JL, Rutheford J, Wertheimer JH, Hawkins CM. on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med 1992; 327: 669-77.
- 5 Wright RA, Flapan AD, Alberti KG, Ludlam CA, Fox KA. Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol 1994; 24: 67-73.
- 6 Hamdan AD, Quist WC, Gagne JB, Feener EP. Angiotensin-converting enzyme inhibition suppresses plasminogen activator inhibitor-1 expression in the neointima of baloon-injured rat aorta. Circulation 1996; 93: 1073-8.
- 7 Vaughan DE, Rouleau J-L, Ridker PM, Arnold JMO, Menapace FJ, Pfeffer MA. on behalf of the HEART study investigators. Effect of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation 1997; 96: 442-7.
- 8 Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, Singel D, Valeri CR, Loscalzo J. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sci USA 1992; 89: 7674-7.
- 9 Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitropruside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Therap 1981; 218: 739-49.
- 10 Mendelsohn ME, O’Neill S, George D, Loscalzo J. Inhibition of fibrinogen binding to human platelets by S-nitroso-N-acetylcysteine. J Biol Chem 1990; 265: 19028-34.
- 11 Radomski MW, Rees Dutra A, Moncada S. S-nitroso-glutathione inhibits platelet activation in vitro and in vivo. Br J Pharmacol 1992; 107: 745-9.
- 12 Pepine CJ. Ongoing clinical trials of angiotensin-converting enzyme inhibitors for treatment of coronary artery disease in patients with preserved left ventricular function. J Am Coll Cardiol 1996; 27: 1048-52.
- 13 Zatz R. A low-cost tail-cuff method for the estimation of mean arterial pressure in conscious rats. Lab Anim Sci 1990; 42: 198-201.
- 14 Reyers I, DeGaetano G, Donati MB. Venostasis-induced thrombosis in rat is not influenced by circulating platelet or leukocyte number. Agents Actions 1989; 28: 137-40.
- 15 Born BVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-95.
- 16 Lahera V, Salom MG, Miranda-Guardiola F, Moncada S, Romero JC. Effects of NG-nitro-L-arginine methyl ester on renal function and blood pressure. Am J Physiol 1991; 261: F1033-F7.
- 17 Swies J, Chlopicki S, Gryglewski RJ. Kinins and thrombolysis. J Physiol Pharmacol 1993; 44: 171-7.
- 18 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
- 19 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995; 95: 995-1001.
- 20 Gryglewski RJ, Botting RM, Vane JR. Mediators produced by the endothelial cell. Hypertension 1988; 12: 530-48.
- 21 Hornstra G, Kalafusz R, Wierts JW, Kester ADM. Does platelet function in vitro reflect thrombosis tendency in vivo?. Thromb Haemost 1991; 65: 1085.
- 22 Schaub RG, Simmons CA, Koets MH, Romano PJ, Steward GJ. Early events in the formation of a venous thrombus following local trauma and stasis. Lab Invest 1984; 51: 218-24.
- 23 Langford EJ, Brown AS, Wainwright RJ, deBelder AJ, Thomas MR, Smith RE, Radomski MW, Martin JF, Moncada S. Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty. Lancet 1994; 344: 1458-60.
- 24 De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone Jr MA, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995; 96: 60-8.
- 25 Wise H. The inhibitory effects of non-prostanoid prostacyclin mimetics on rat neutrophil function. Prostaglandins Leukot Essent Fatty Acids 1996; 54: 351-60.