Attenuation by prolonged nitric oxide synthase inhibition of the enhancement of fibrinolysis caused by environmental stress in the rat.
1. Nitric oxide (NO) suppresses platelet aggregation and plasminogen activator inhibitor (PAI) release from platelets, playing physiological and/or pathological roles in the haemostatic system. We investigated the effect of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, on the disseminated intravascular coagulation (DIC)-like phenomena in rats under environmental stress, induced by prolonged fluctuation in air temperature, known as SART (specific alternation of rhythm in temperature) stress. 2. Exposure of rats to SART stress for 7 days caused mild DIC-like symptoms such as thrombocytopenia, hypofibrinogenemia, decreased factor VIII: coagulant activity and shortened euglobulin clot lysis time (ECLT). The enhanced fibrinolysis was accompanied by a marked decrease in the activity of plasma PAI. 3. L-NAME, but not its D-enantiomer, when administered orally at 0.3-10 mg kg-1, twice a day for 7-day exposure to stress, inhibited the stress-induced decrease in fibrinogen levels in a dose-dependent manner, whereas it failed to alter platelet count, factor VIII:coagulant activity and plasma protein levels in stressed rats. All these parameters in unstressed rats were resistant to L-NAME at 10 mg kg-1. 4. Repeated treatment with 10 mg kg-1 of L-NAME blocked the shortening of ECLT and the decrease in PAI activity following stress exposure, although it was without effect in unstressed rats. 5. The inhibitory effects of L-NAME at 10 mg kg-1 on the stress-induced alterations in fibrinogen levels and in ECLT were significantly reduced by coadministered L-arginine at 1000 mg kg-1. 6. These findings demonstrate that repeated administration of L-NAME attenuates the enhanced fibrinolysis, without aggravating thrombocytopenia, in SART-stressed rats. Endogenous NO appears to contribute to the stress-induced development of fibrinolysis by suppressing, plasma PAI activity, most probably as a result of inhibition of the PAI release from platelets.
Kawabata
A
A
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
Hata
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T
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001779:Blood Coagulation Factors / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012712:Serum Globulins / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013312:Stress, Physiological / Q000097:blood*
D001779:Blood Coagulation Factors; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D012712:Serum Globulins; D005340:Fibrinogen; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester