RESUMO
AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS: Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed. RESULTS: The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION: These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.
Assuntos
Aspirina/farmacologia , Plaquetas/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Hipertensão Portal/sangue , Nitrobenzenos/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Pirazóis/farmacologia , Sulfonamidas/farmacologia , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Plaquetas/fisiologia , Dinoprostona/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lasers/efeitos adversos , Leucotrieno B4/sangue , Masculino , Ratos , Ratos Wistar , Trombose/sangue , Trombose/etiologia , Tromboxano B2/sangueRESUMO
In our previous study, we demonstrated the effect of ultralow-dose aspirin (ULDA) on platelet activity and bleeding in rats with portal hypertension (PHT) produced by portal vein ligation (PVL). This paper reports modifications in this effect caused by blocking NO production by nitro arginine methyl ester (NAME) and cyclooxygenase (COX) activity with indomethacin. PVL rats and sham-operated controls were treated with placebo, indomethacin or NAME and 30 min thereafter with placebo or ULDA treatment. Platelet activity was studied by a model of in vivo laser-induced thrombus production in the mesenteric circulation, induced hemorrhage time (IHT) and platelet aggregation ex vivo induced by adenosine diphosphate in an aggregometer. The PVL group receiving placebo showed a decreased platelet activity with prolonged IHT, an effect that was reversed by ULDA. Indomethacin induced a decreased platelet activity in the control rats and a prolonged IHT. In PHT with ULDA, in vivo platelet activity was enhanced but the normalization of IHT observed in rats without indomethacin was blunted. The addition of NAME normalized the diminished in vivo platelet aggregation and increased the IHT observed in PVL animals. These changes decreased the effect of ULDA in both sham-operated and PVL animals. The effect of indomethacin was more clearly modified by ULDA than the effect of NAME, thus suggesting that modifications in the COX pathway might alter the effect of ULDA. The simultaneous administration of indomethacin and ULDA could inhibit its beneficial effect on bleeding in rats with PHT.
Assuntos
Aspirina/administração & dosagem , Hipertensão Portal/tratamento farmacológico , Indometacina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Ativação Plaquetária/efeitos dos fármacos , Animais , Aspirina/farmacologia , Testes de Coagulação Sanguínea , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Interações Medicamentosas , Indometacina/administração & dosagem , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Testes de Função Plaquetária , Ratos , Ratos Wistar , Circulação Esplâncnica , TromboseRESUMO
Aspirin (ASA) is widely accepted as antithrombotic drug, but several reports point out that its use in ultra-low doses (ULD) has prothrombotic properties. In this study, we evaluate the effect of portal hypertension in rats on platelet aggregation in an in vivo arterial thrombosis model induced by a laser beam. Portal hypertension was produced by calibrated stenosis of the portal vein. ASA in ULD was injected to both control and portal hypertensive groups. Platelet aggregation induced by ADP, prothrombin time, activated partial thromboplastin time, fibrinogen and induced hemorrhagic time test were also performed. Portal hypertensive rats showed a diminished number of emboli and duration of embolization in the laser procedure and an increase in induced hemorrhagic time. These changes were reverted by one injection of ASA at ULD. This observation could be of importance for primary prevention or the treatment of recurrence in upper digestive tract hemorrhage in portal hypertensive patients.
Assuntos
Aspirina/administração & dosagem , Hipertensão Portal/sangue , Inibidores da Agregação Plaquetária/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/administração & dosagem , Animais , Fibrinogênio/análise , Hemorragia/sangue , Hemorragia/induzido quimicamente , Humanos , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Injeções Subcutâneas , Masculino , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Ratos , Ratos WistarRESUMO
AIM: To study the blood-brain barrier integrity, brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS: Adults male Wistar rats were divided into four groups. Group I: sham operation; II: Prehepatic portal hypertension, produced by partial portal vein ligation; III: Acetaminophen intoxication and IV: Prehepatic portal hypertension plus acetaminophen. Acetaminophen was administered to produce acute hepatic injury. Portal pressure, liver serum enzymes and ammonia plasma levels were determined. Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity. Reflexes and behavioral tests were recorded. RESULTS: Portal hypertension was significantly elevated in groups II and IV. Liver enzymes and ammonia plasma levels were increased in groups II, III and IV. Prehepatic portal hypertension (group II), acetaminophen intoxication (group III) and both (group IV) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia. Cortical edema was present in rats with acute hepatic injury in groups III and IV. Behavioral test (rota rod) was altered in group IV. CONCLUSION: These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (cytotoxic). Group IV, with behavioral altered test, can be considered as a model for study at an early stage of portal-systemic encephalopathy.