RESUMO
OBJECTIVE: To investigate the effects of prostacyclin (PGI(2)) and nitric oxide (NO) in the development of hyperdynamic circulatory state on chronic portal hypertensive rats. METHODS: Sixty-six male SD rats were divided into three groups, namely intrahepatic portal hypertension (IHPH) by injection of CCl(4), prehepatic portal hypertension (PHPH) by partial stenosis of the portal vein for 2 weeks and sham-operated controls (SO). Animals in each group were divided further into 3 subgroups and received N(omega)-nitro-L-arginine (L-NNA), indomethacin and saline (as control), respectively. Splanchnic and systemic hemodynamics was measured using radioactive microsphere techniques. The NO concentration in serum was determined by nitrates-nitrites which were measured using a colorimetric method, and concentration of PGI(2) was determined using specific radioimmunoassay for its stable hydrolytic product, 6-keto-PGF(1 alpha). RESULTS: The concentrations of plasma 6-keto-PGF(1 alpha) and serum nitrates + nitrites in IHPH rats (1 123.85 +/- 153.64; 73.34 +/- 4.31) and in PHPH rats (891.88 +/- 83.11; 75.21 +/- 6.89) were significantly higher than those of SO rats (725.53 +/- 105.54;58.79 +/- 8.47). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGF(1 alpha) and serum nitrates + nitrites in IHPH and PHPH rats (P < 0.05). At the same time, CI, FPP and PVI were lowered while MAP, TPR and SVR were increased (P < 0.05). After deduction of NO action, there were no significant correlation between plasma PGI(2) level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of PGI(2) action, NO was still correlated highly with those hemodynamic parameters. CONCLUSION: It is NO rather then PGI(2) that is a mediator in the formation and development of hyperdynamic circulatory state in chronic portal hypertensive rats.
Assuntos
Epoprostenol/fisiologia , Hipertensão Portal/fisiopatologia , 6-Cetoprostaglandina F1 alfa/sangue , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epoprostenol/sangue , Hemodinâmica/efeitos dos fármacos , Hipertensão Portal/sangue , Masculino , Óxido Nítrico/sangue , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , ômega-N-Metilarginina/farmacologiaRESUMO
Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may be due to their cholesterol-lowering independent effects on the blood vessels. Chronic inhibition of endothelial nitric oxide (NO) synthesis by oral administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats induces early vascular inflammation as well as subsequent arteriosclerosis. The aim of the study is to test whether treatment with statins attenuates such arteriosclerotic changes through their cholesterol-lowering independent effects. We investigated the effect of statins (pravastatin and cerivastatin) on the arteriosclerotic changes in the rat model. We found that treatment with statins did not affect serum lipid levels but markedly inhibited the L-NAME-induced vascular inflammation and arteriosclerosis. Treatment with statins augmented endothelial NO synthase activity in L-NAME-treated rats. We also found the L-NAME induced increase in Rho membrane translocation in hearts and its prevention by statins. Such vasculoprotective effects of statins were suppressed by the higher dose of L-NAME. In summary, in this study, we found that statins such as pravastatin and cerivastatin inhibited vascular inflammation and arteriosclerosis through their lipid-lowering independent actions in this model. Such antiarteriosclerotic effects may involve the increase in endothelial NO synthase activity and the inhibition of Rho activity.
Assuntos
Anti-Inflamatórios/farmacologia , Arteriosclerose/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Quimiocina CCL2/genética , Vasos Coronários/química , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Lipídeos/sangue , Macrófagos/imunologia , Masculino , Monócitos/imunologia , NG-Nitroarginina Metil Éster/farmacologia , Nitratos/sangue , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Nitroarginina/sangue , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Pravastatina/sangue , Pravastatina/farmacologia , Antígeno Nuclear de Célula em Proliferação/análise , Piridinas/sangue , Piridinas/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKY , Sístole , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta1 , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
In this paper, the HPLC method for the measurement of nitrite and nitrate in serum of humans newly reported by E1 Menyawi et al. is discussed, especially in regard to the extremely low nitrate levels measured in serum of healthy humans. From the discussion, it is concluded that: (1) Biogenic amines at physiological concentrations do not significantly interfere with the batch Griess assay. (2) The HPLC method of E1 Menyawi et al. does not reveal accurate levels for serum nitrate. (3) In serum and plasma of healthy humans, nitrate ranges within 15-70 microM. (4) Exogenous NG-nitro-L-arginine analogs can interfere with the measurement of nitrate in human plasma and urine by the batch Griess assay, chemiluminescence and GC-MS; interferences can be effectively eliminated by solid-phase extraction on cation-exchangers.