Hemostasis imbalance in experimental hypertension.
BACKGROUND
The rat model of chronic intoxication by N(G) -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.


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.
Corseaux
Delphine
D
INSERM U479, Faculté Xavier Bichat, Paris, France.
Ollivier
Véronique
V
Fontaine
Vincent
V
Huisse
Marie-Geneviève
MG
Philippe
Monique
M
Louedec
Liliane
L
Vranckx
Roger
R
Ravanat
Catherine
C
Lanza
François
F
Angles-Cano
Edouardo
E
Guillin
Marie-Claude
MC
Michel
Jean-Baptiste
JB
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D001158:Arteries / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000378:metabolism; D006321:Heart / Q000033:anatomy & histology; D006487:Hemostasis / Q000502:physiology*; D006973:Hypertension / Q000097:blood* / Q000139:chemically induced; D007678:Kidney Glomerulus / Q000033:anatomy & histology / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009929:Organ Size; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D019331:NG-Nitroarginine Methyl Ester