RESUMO
The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.
Assuntos
Antitrombinas/farmacologia , Ácidos Pipecólicos/farmacologia , Líquido Sinovial/metabolismo , Trombina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Arginina/análogos & derivados , Coagulação Sanguínea/efeitos dos fármacos , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Sulfonamidas , Líquido Sinovial/efeitos dos fármacos , Tromboplastina/metabolismoRESUMO
A new gating NMR technique triggered by pulses for the cardiac pacing of isolated, perfused rat heart is described. This technique is suitable for obtaining spectra at the same positions over the cardiac cycle with the same RF pulse repetition time and with constant heart rate. Accordingly, each recovered magnetization level at these positions during the cycle can be kept constant. It also allows a qualitative analysis of the myocardial energy level during the cycle under the condition of the same or different cardiac workload (rate pressure product, HR x LVP). This method was used to observe cyclical changes in the concentration of adenosine triphosphate (ATP), phosphocreatine (PCr), P(i), and in pH during the cardiac cycle, and confirmed that the levels of ATP and PCr showed reversible decreases, and P(i) showed an antiphasic increase at the peak systole. On the other hand, no significant changes in pH were noted during the cardiac cycle. This pacing-gated technique is an improvement over other gated NMR techniques triggered by the blood pressure or by ECG traces.