• 作者： 廖美惠; 吳錦楨; 顏茂雄
• 作者服務機構： 國防醫學院藥理學科
• 中文摘要： Tetramethylpyrazine（中藥川芎的一主成份），也是一種phosphodiesterase抑制劑，長期在中國大陸被用來改善心血管疾病。此研究動機在探討tetramethylpyrazine對內毒素在大鼠所引起的低血壓、血管低反應性和腫瘤壞死因子及一氧化氮的釋出之影響。結果顯示，大鼠經內毒素(10 mg/kg, i.v.)注射後會引起低血壓和心跳加快的現象，tetramethylpy-razine (10 mg/kg, i.p.)可使血壓回升但卻使心跳有更加快的趨勢。內毒素也會引起對norepinephrine (NE)的升壓（活體；1 μg/kg, i.v.）和收縮（離體；1 μM）反應變差，而大鼠在經tetramethylpyrazine預處理後，皆可部份改善此血管低反應性的現象。內毒素會導致血中腫瘤壞死因子及一氧化氮濃度的上升，而此作用可被tetramethylpyrazine所部份拮抗。另外，tetramethylpyrazine也可部份改善內毒素所引發的早期低血壓作用，由 acetylcholine (ACh; 1 μM)的舒張反應證實tetramethylpyrazine並不影響內皮型一氧化氮合成酵素的活性（因ACh的舒張反應不受tetramethylpyrazine的影響）。因此，tetramethylpyrazine改善內毒素所引起的低血壓作用可能是經由減少循環因子（活化內皮型一氧化氮合成酵素）和腫瘤壞死因子的釋出進而阻斷誘導型一氧化氮合成酵素的生成所致。
• 英文摘要： Tetramethylpyrazine, an inhibitor of phosphodiesterase, has been widely used for treatment of car-diovascular diseases in China. Here, we investigate the effects of tetramethylpyrazine on hypotension,vascular hyporeactivity to norepinephrine (NE), release of tumor necrosis factor-α (TNFα) and nitric oxide(NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS).Male Wistar-Kyoto rats were anesthetized and instrumented for the measurement of mean arterial pressure(MAP) and heart rate (HR). Injection of LPS (10 mg/kg, i.v.) resulted in a fall in MAP and an increase ofHR. In contrast, animals pretreated with tetramethylpyrazine (10 μg/kg, i.p. at 30 min prior to LPS) main-tained a significantly higher MAP, but tachycardia was further enhanced at 60 min and 120 min when com-pared to rats given only LPS (LPS-rats). The pressor effect of NE (1 μg/kg, i.v.) was also significantlyreduced after treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats after in vivostudies showed a significant reduction in the contractile responses elicited by NE (1 μM). Pretreatment ofLPS-rats with tetramethylpyrazine partially, but significantly, prevented this LPS-induced hyporeactivityto NE in vivo and ex vivo. The injection of LPS resulted in a significant increase in the plasma TNFα levelat 60 min, whereas the effect of LPS on the plasma nitrate (an indicator of NO formation) level increased in atime-dependent manner. This increment of both TNFα and nitrate levels induced by LPS was signifi-cantly reduced in LPS-rats pretreated with tetramethylpyrazine. The early hypotension caused by LPSwas slightly, but significantly, prevented by pretreatment with tetramethylpyrazine, suggesting thattetramethylpyrazine affects the endothelial constitutive NOS (eNOS). This was examined by the effectof tetramethylpyrazine on acetylcholine (ACh, 1 μM)-induced relaxation in rats treated withtetramethylpyrazine for 4 h. However, tetramethylpyrazine had no significant effects on the ACh-inducedrelaxation, indicating that tetramethylpyrazine does not affect the activity of eNOS. Thus, tetramethylpyrazineattenuates the early hypotension and the delayed circulatory failure caused by endotoxin in the rat. Theseeffects may be due to inhibition of the release of circulation factors and TNFα, which usually reveal syner-gism upon the induction of iNOS.
• 中文關鍵字： tetramethylpyrazine; tumor necrosis factor-α; nitric oxide; lipopolysaccharide; endoxtoxemia.
• 英文關鍵字： --