N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity
N-hydroxy-pyrroline modification of verapamil exhibits antioxidant protection of the heart against ischemia/reperfusion-induced cardiac dysfunction without compromising its calcium antagonistic activity
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DOI：
10.1124/jpet.107.127167
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发表时间：
2007-10-01
影响因子：
3.5
通讯作者：
Kuppusamy, Periannan
中科院分区：
文献类型：
--
作者：
Mandal, Rajarsi;Kutala, Vijay Kumar;Kuppusamy, Periannan
任何用于将血流重新引入心肌缺血区域的临床干预措施（例如冠状动脉血管成形术、溶栓术）都伴随着复杂的酶级联反应，导致心脏严重损伤，称为心肌缺血/再灌注（I/R）损伤。在本研究中，我们评估了 H-3010(1-羟基-2,2,5,5-四甲基2,5-二氢-1H-吡咯-3-羧酸(2-(3,4-二甲氧基苯基)5-([2-(3,4-二甲氧基苯基)乙基]-甲氨基)-2异丙基戊基)-酰胺)的能力， 维拉帕米（2-(3,4-二甲氧基苯基)-5-[2-(3,4-二甲氧基苯基)乙基甲基氨基]-2-(1-甲基乙基)戊腈）的吡咯啉修饰，可保护心脏免受缺血再灌注介导的损伤。用维拉帕米和 H-3010 预处理的离体灌注大鼠心脏经历 30 分钟的整体无血流缺血，然后进行 45 分钟的再灌注。与使用 5 μM 维拉帕米 (32.2 +/- 3.7%) 或未经处理的对照心脏相比，使用 5 μM (51.0 +/- 6.4%) 和 50 μM (75.1 +/- 7.4%) H-3010 处理的心脏的收缩功能（左心室发展压力）的恢复（表示为缺血前基线的百分比）显着更高 （18.1 +/- 2.8%）。与未经处理的对照组（131.5 +/- 6.4 U/升）相比，经 H-3010 处理的心脏（45.7 +/- 4.5 U/升）肌酸激酶释放显着减弱。对于乳酸脱氢酶的释放也观察到类似的趋势。与维拉帕米组 (25.1 +/- 2.9%) 和对照组 (41.3 +/- 1.9%) 相比，H-3010 组中观察到梗塞面积百分比显着降低 (11.7 +/- 1.6%)。其他体外研究表明，H-3010 显着减少了活性氧的产生。总之，我们的数据清楚地表明维拉帕米衍生物 H-3010 可显着降低缺血再灌注引起的心脏功能障碍。这可以归因于吡咯啉部分（抗氧化剂）和母体维拉帕米成分（抗心律失常药）在保护心脏免受缺血再灌注引起的损伤方面的综合益处。
Any clinical intervention ( e. g., coronary angioplasty, thrombolysis) used to reintroduce blood flow to an ischemic region of the myocardium is accompanied by a complex enzymatic cascade of reactions resulting in severe injury to the heart, termed myocardial ischemia/reperfusion (I/R) injury. In this study, we evaluated the ability of H-3010(1-hydroxy-2,2,5,5-tetramethyl2,5- dihydro-1H-pyrrole-3-carboxylic acid (2-(3,4-dimethoxyphenyl)5-([2-(3,4- dimethoxyphenyl) ethyl]-methylamino)-2isopropylpentyl)-amide), a pyrroline modification of verapamil ( 2-( 3,4- dimethoxyphenyl)-5-[2-(3,4- dimethoxyphenyl) ethylmethylamino]-2-(1-methylethyl)pentanenitrile), to protect the heart against I/R-mediated injury. Isolated perfused rat hearts pretreated with verapamil and H-3010 were subjected to 30 min of global no-flow ischemia followed by 45 min of reperfusion. The recovery ( expressed as a percentage of preischemic baseline) in contractile function ( left ventricular developed pressure) of hearts subjected to I/R was significantly higher in hearts treated with H-3010 at 5 mu M (51.0 +/- 6.4%) as well as at 50 mu M (75.1 +/- 7.4%) as compared with verapamil at 5 mu M ( 32.2 +/- 3.7%) or untreated control hearts (18.1 +/- 2.8%). Creatine kinase release was significantly attenuated in hearts treated with H-3010 ( 45.7 +/- 4.5 U/liter) as compared with untreated controls ( 131.5 +/- 6.4 U/liter). Similar trends were also observed for lactate dehydrogenase release as well. A marked reduction in percent area of infarction was observed in the H- 3010 group ( 11.7 +/- 1.6%) compared with verapamil (25.1 +/- 2.9%) and control ( 41.3 +/- 1.9%) groups. Additional in vitro studies showed a marked decrease in reactive oxygen species generation with H-3010. In conclusion, our data clearly demonstrated that the verapamil derivative, H- 3010, significantly decreased I/R-induced cardiac dysfunction. This can be attributed to the combined benefits of the pyrroline moiety (antioxidant) and the parent verapamil component (antiarrhythmic) in the protection of the heart from I/R-induced injury.