Protective Effects of Phosphodiesterase Inhibition on Heart Against Ischemia-Reperfusion Induced Injury and Apoptosis in Rats

• Main Authors: Chi-Hou Ho, 何志豪
• Other Authors: Ing-Jun Chen
• Format: Others
• Language: zh-TW
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/95370494895935214512

碩士 === 高雄醫學大學 === 醫學研究所 === 91 === KMUP-1, a new xanthine derivative and antagonist of α—adrenoaceptor, possesses the guanylyl cyclase stimulating, potassium channel opening, and phosphodiesterase inhibition activities. The present study is designed to investigate whether administration of KMUP-1 may reduce apoptosis and myocardial infarct size or not, and thus attributed to its anti-ischemic and cardioprotective actions. The effects of KMUP-1 against myocardial reperfusion injury in rats were subjected to left anterior descending coronary artery (LAD) occlusion for 45 min and then followed by reperfusion for 1h. Rats were treated with vehicle or KMUP-1 (0.25 or 0.5 mg/kg, i.v.) 10 min before coronary artery occlusion. In the vehicle-treated group, ischemia/reperfusion-caused cardiomyocyte apoptosis was evidenced by DNA ladder formation technique. Treatment with 0.25 mg/kg and 0.5 mg/kg KMUP-1 lowered blood pressure, decrease myocardial apoptosis and necrosis, increased serum NO concentration (20.56 ± 1.23 and 28.05 ± 4.89, P < 0.05 vs vehicle) and reduced infarct size (18.69 ± 0.55 and 8.2 ± 0.22, P < 0.01 vs vehicle). In addition, treatment with KMUP-1 could reduce cardiac oxygen consumption, increase eNOS protein expression (219.21 ± 13.45 ﹪and 239.50 ± 13.82 ﹪, P < 0.05 vs vehicle (161.67 ± 12.82 ﹪) ), decrease iNOS protein expression (106.13 ± 0.16 ﹪and 105.65 ± 0.22 ﹪, vs vehicle (115.90 ± 0.19 ﹪) ), decrease PDE V protein expression (68.40 ± 5.95 ﹪and 61.10 ± 7.45 ﹪, vs P < 0.05 vehicle 103.35 ± 7.30 ﹪), decrease CK-MB (2238.88 ± 310.83 and 1940.00 ± 385.30, P < 0.05 vs vehicle), LDH (1825.25 ± 271.94 and 1727.75 ± 271.51, P < 0.05 vs vehicle) and MPO (0.74 ± 0.08 and 0.71 ± 0.04, P < 0.05 vs vehicle). Elevated plasma CK-MB, LDH and MPO activity by ischemia-reperfusion were reduced by KMUP-1. Inhibition of phosphodiesterase enhances NO-mediated protection against myocardial injury. Administration of KMUP-1 (0.5 mg/kg) produced favorable haemodynamic effects, provided the additional protection against myocardial necrotic injury, and further improved the recovery of cardiac function. In conclusion, the present data provided the evidences that KMUP-1 may activate NO/sGC/cGMP pathway, enhance eNOS protein expression, stimulate K+ channel, inhibit phosphodiesterase activities, and thus reduce ischemia/ reperfusion-induced cardiac injury.