Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction
Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction
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DOI：
10.1097/01.fjc.0000250077.07702.23
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发表时间：
2006-12-01
影响因子：
3
通讯作者：
Dambrova, Maija
中科院分区：
文献类型：
--
作者：
Liepinsh, Edgars;Vilskersts, Reinis;Dambrova, Maija
抑制γ -丁甜菜碱（GBB）羟化酶是肉碱生物合成的关键酶，为米屈酸钠的心脏保护机制奠定了基础。通过抑制肉碱的生物合成，米屈酸盐被认为可以诱导GBB的积累，GBB是GBB羟化酶的底物。本研究描述了米屈酸钠长期（28天）治疗大鼠血浆和心脏组织中肉碱和GBB含量的变化。（腹腔内）100mg /kg/日]。获得的数据表明，在肉碱浓度下降的同时，米屈酸钠的施用导致GBB浓度显著增加。我们发现血浆和大脑中的GBB含量增加了5倍，心脏中的GBB含量增加了7倍。此外，我们在离体大鼠心肌梗死模型中测试了米膦酸钠在给药3、7和14天后的心脏保护作用。我们发现，在米屈酸钠治疗14天后，梗死大鼠心脏的坏死面积有统计学意义的减少。米屈酸钠的心脏保护作用与GBB含量的增加相关。综上所述，我们的研究首次提供了实验证据，证明长期服用米膦酸盐不仅可以降低游离肉碱浓度，还可以导致GBB浓度显著升高，这与米膦酸盐的心脏保护作用有关。
The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.