Wang Hong-Lan, Dai De-Zai, Gao Eeng, Zhang Yan-Pin, Lu Feng
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2004 Jun;25(6):738-43.
To investigate the effect of CPU86017 on the changes of mRNA abundance of different calcium handling system in infarcted heart.
Rats were subjected to left coronary ligation to induce myocardial infarction (MI). The treatment with either propranolol (Pro) 5 mg/kg ip or CPU86017 1, 2, and 4 mg/kg ip was initiated on the next day of operation and continued for 20 d. Medication with isoproterenol (Isop) 3 mg/kg sc started on the d 17-21. Ventricular mRNA abundance of ryanodine receptor 2 (RyR2), sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), L-type Ca(2+) channel, and Na(+)/Ca(2+)exchanger (NCX1) were measured.
Arrhythmic scores (AS) in the Isop group was raised up to 5.27+/-1.75 (P<0.01) vs myocardial infarction group 2.25+/-2.04 and sham group 1.50+/-1.73. The AS was depressed by Pro (1.63+/-1.53, P<0.01 vs Isop), and CPU86017 2 and 4 mg/kg (3.00+/-1.24, and 1.70+/-1.85, P<0.01 vs Isop). The significant dispersion of depressed mRNA abundance of RyR2 and SERCA2 was associated with an increase in AS in Isop group, and it was much depressed in the left than the right ventricle. The dispersion and depression of mRNA were restored significantly by Pro and CPU86017, associated with suppression on AS. In Isop group, the mRNA abundance of L-type Ca(2+) channel was not changed; and a moderate increase in the mRNA of NCX1 was seen, the changes were regressed by Pro and CPU86017.
Isop-induced arrhythmogenesis in MI heart was correlated mainly with a dispersion of depressed mRNA abundance in ventricle likely due to the consequence of PKA over-phosphorylation. A suppression of arrhythmia by Pro and CPU86017 resulted from a regression of the dispersion and depression of RyR2 and SERCA2.
研究CPU86017对梗死心脏中不同钙处理系统mRNA丰度变化的影响。
通过结扎大鼠左冠状动脉诱导心肌梗死（MI）。在手术次日开始腹腔注射普萘洛尔（Pro）5mg/kg或CPU86017 1、2和4mg/kg进行治疗，并持续20天。在第17 - 21天开始皮下注射异丙肾上腺素（Isop）3mg/kg。检测心室中兰尼碱受体2（RyR2）、肌浆网Ca(2 +)-ATP酶（SERCA2）、L型Ca(2 +)通道和Na(+)/Ca(2 +)交换体（NCX1）的mRNA丰度。
与心肌梗死组（2.25±2.04）和假手术组（1.50±1.73）相比，Isop组的心律失常评分（AS）升高至5.27±1.75（P<0.01）。Pro（1.63±1.53，与Isop组相比P<0.01）以及CPU86017 2mg/kg和4mg/kg（3.00±1.24和1.70±1.85，与Isop组相比P<0.01）可降低AS。Isop组中RyR2和SERCA2的mRNA丰度显著分散且与AS增加相关，并且左心室的降低程度远大于右心室。Pro和CPU86017可显著恢复mRNA的分散和降低，同时抑制AS。在Isop组中，L型Ca(2 +)通道的mRNA丰度未改变；NCX1的mRNA有适度增加，Pro和CPU86017可使这些变化逆转。
Isop诱导MI心脏心律失常主要与心室中mRNA丰度降低的分散有关，这可能是PKA过度磷酸化的结果。Pro和CPU86017对心律失常的抑制作用源于RyR2和SERCA2分散和降低的逆转。
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