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Hemostasis Imbalance in Experimental Hypertension

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Abstract

Background

The rat model of chronic intoxication by NG-nitro-l-arginine methyl ester (l-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events.

Methods and Results

Administration of l-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5′-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels.

Conclusions

These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.

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Acknowledgments

This work was supported by grants from Menarini (Florence, Italy) and by INSERM. D.C. was supported by the Society of Nephrology and V.F. by the French Society of Hypertension. We thank Pierre-Louis Tharaux and Christos Chatziantoniou for their assistance with the isolation of renal arterioles.

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Authors and Affiliations

  1. INSERM U479, Faculté Xavier Bichat, BP 416, 75870, Paris CEDEX 18, France

    Delphine Corseaux & Véronique Ollivier

  2. INSERM E9907, Faculté Xavier Bichat, Paris, France

    Marie-Geneviève Huisse & Marie-Claude Guillin

  3. INSERM U460, Faculté Xavier Bichat, Paris, France

    Vincent Fontaine, Monique Philippe, Liliane Louedec, Roger Vranckx, Edouardo Angles-Cano & Jean-Baptiste Michel

  4. INSERM U311, Etablissement Français du Sang, Strasbourg, France

    Catherine Ravanat & François Lanza

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  1. Delphine Corseaux
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  3. Vincent Fontaine
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Correspondence to Véronique Ollivier.

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D.C. and V.O. contributed equally to this work.

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Corseaux, D., Ollivier, V., Fontaine, V. et al. Hemostasis Imbalance in Experimental Hypertension. Mol Med 8, 169–178 (2002). https://doi.org/10.1007/BF03402009

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