| Summary: | 碩士 === 高雄醫學大學 === 藥理學研究所碩士班 === 94 === It is known that chronic treatment of a ??-adrenergic agonist, isoproterenol, induced cardiac hypertrophy. Another model, spontaneously hypertensive rats (SHR) also developed chronic hypertension leading to cardiac hypertrophy and heart failure. When given of NOS inhibitor N-omega-nitro-L-arginine (L-NNA) or KATP channel blockor 5-hydroxydecanoate (5-HD), aggravated the response of cardiac hypertrophy. The present study investigated that the in vivo effects of KMUP-1 and sildenafil, phosphodiestrase-5 (PDE-5) inhibitors, on the hypertrophic responses of rat heart to isoproterenol and SHR, and the relation of the effects to the levels of myocardial cyclic guanosine monophosphate (cGMP) and nitric oxide, the activities of PKG, NOS, GSK3-???z?ncalcineurin A and ERK1/2.
The results showed that daily subcutaneous administration of isoproterenol for 10 days caused significantly cardiac hypertrophy, cell injury and decline in survival. Treatment of L-NNA (20 mg/l/day) in SHR also developed significantly cardiac hypertrophy and decline in survival. KMUP-1 (0.5 mg/kg/day) and sildenafil (0.7 mg/kg/day) were intraperitoneal injected, one hour before isoproterenol. KMUP-1 and sildenafil was also intraperitoneal injected to SHR. We found that both KMUP-1 and sildenafil significantly improved the survival rate and decreased the ratio of heart weight to body weight (HW/BW). Both KMUP-1 and sildenafil increased the expression of eNOS, PKG and GSK-3??, and the production of NO and cGMP, but suppressed the expression of iNOS, calcineurin A and ERK1/2. However these effects of KMUP-1 and sildenafil were partially reversed by treatment of L-NNA and 5-HD.
These present study indicated that KMUP-1 similar to sildenafil has a cardioprotective effect against isoproterenol- and spontaneously hypertension-induced myocardial cell injury. KMUP-1 may through the activation NO/cGMP/PKG-1 pathway and then to improve survival rate and cardiac function, suggesting that it may have great potential in the prevention of cardiac hypertrophy and heart failure.
|
|---|
