KMUP-1減少Isoproterenol和自發性高血壓所誘發大鼠的心肌肥厚之研究

KMUP-1 attenuates isoproterenol- and spontaneously hypertension-induced cardiac hypertrophy of rats

吳秉儒(Ping-Ju Wu)

指導教授 ： 葉竹來

高雄醫學大學/醫學院/藥理學科研究所/碩士(2006年)

摘要

已有研究指出長期給予腎上腺素性乙型受體作用劑Isoproterenol可誘導心肌肥大的產生。另一種模式，自發性高血壓大鼠因長期自身的高血壓，也會導致心肌肥大和心衰竭。而一氧化氮合成酶抑制劑N-omega-nitro-L-arginine (L-NNA) 和ATP敏感型鉀離子通道阻斷劑 5-hydroxydecanoate (5-HD)則會讓心肌肥大的情形更加惡化。在本實驗擬探討第五型的磷酸二酯酶抑制劑KMUP-1和Sildenafil，在活體實驗中對於Isoproterenol所誘導心肌肥大或是自發性高血壓所產生的心肌肥大之影響，並觀察KMUP-1和Sildenafil對於cGMP和一氧化氮濃度以及在PKG、NOS、GSK-3?牷Bcalcineurin A 和ERK1/2之間的調控作用。
由實驗結果得知，每天給予大鼠皮下注射Isoproterenol (5毫克/公斤/天) 為期10天，可明顯地導致心肌肥大、心臟細胞受損及降低存活率。而給予自發性高血壓大鼠L-NNA (20毫克/升/天)，也會增加心肌的肥大情形和降低存活率。在給予Isoproterenol的前一個小時，腹腔注射KMUP-1 (0.5毫克/公斤/天) 和Sildenafil (0.7毫克/公斤/天)，在自發性高血壓大鼠也以腹腔注射KMUP-1 (0.5毫克/公斤/天)和Sildenafil (0.7毫克/公斤/天)。我們發現KMUP-1和Sildenafil可明顯地改善大鼠的存活率及減少心臟和體重的比率。KMUP-1和
Sildenafil會增加eNOS、PKG、GSK-3?猁漯穛{和cGMP及一氧化氮濃度，但是會降低iNOS、calcineurin A和ERK1/2的表現。然而，KMUP-1和Sildenafil所引起的作用會被L-NNA和5-HD所部份抑制。
從本實驗得知KMUP-1具有和Sildenafil相似的心臟保護作用，可防止Isoproterenol或是自發性高血壓所導致的心肌受損。KMUP-1可能是經由活化NO/cGMP/PKG的路徑來改善大鼠存活率及心臟功能，所以KMUP-1可能具有防止心肌肥大及治療心衰竭的功能。

關鍵字

乙型受體作用劑 ； 心肌肥大 ； 自發性高血壓大鼠 ； 一氧化氮合成酶抑制劑 ； ATP敏感型鉀離子通道阻斷劑 ； 第五型磷酸二酯酶抑制劑

並列摘要

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.

並列關鍵字

beta-adrenergic agonist ； cardiac hypertrophy ； SHR ； NOS inhibitor ； KATP channel blockor ； phosphodiestrase-5 inhibitors

參考文獻

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