|Budget Amount *help
¥3,100,000 (Direct Cost : ¥3,100,000)
Fiscal Year 1999 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Proinflammatory cytokines such as interleukin-1β(IL-1β) and tumor necrotic factor-α (TNF-α) contributes to the progression of chronic heart failure (CHF). Treatment with angiotensin converting enzyme (ACE) inhibitor has been show to improve left ventricular (LV) dysfunction and mortality in patients with CHF,few reports have revealed its effect on expression of cytokines during progression of CHF. We investigated the effects of long-term treatment with trandolapril on expression of IL-1β and TNF-α in rats with CHF following left coronary artery ligation. Two weeks after the operation, the rats were randomized to receive either oral administration with trandolapril 3 mg/kg/day for 6 wk or no drug. The levels of IL-1β and TNF-α proteins were measured by ELISA. Treatment with trandolapril attenuated the increases in LVEDP, right ventricular (RV) weight and lung weight and prevented the decreases in ±dP/dt and cardiac output. Plasma concentrations of IL-1β and TNF-α remained undetectable in all groups. As compared with sham rats, there was a significant increase in IL-β protein content in LV scar tissue of rats with CHF (113±7 vs 12±3 mg/protein, P<0.001) and RV IL-1β(19±2 vs 10±1 mg/protein, p<0.05). Treatment with trandolapril significantly attenuated the elevations of these cytokines. IL-1β content in RV significantly correlated with LVEDP (r=0.88, p<0.001) and lung/body weight (r=0.70, p<0.001). In addition, ICE activity in blood was increased in rats with CHF, which was completely prevented by trandolapril. Furthermore, in vitro assay showed that trandolaprilat, an active form of trandolapril, inhibited ICE activity. The results suggest that the beneficial effect of trandolapril is partly due to modification of the enhanced expression of IL-1β possibly through the inhibition of ICE activity.