Takeo Satoshi, Tanonaka Kouichi, Iwai Takeshi, Motegi Kanataka, Hirota Yuko
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Biochem Pharmacol. 2004 Feb 1;67(3):565-74. doi: 10.1016/j.bcp.2003.09.016.
A possible mechanism for D-cis-diltiazem (diltiazem)-mediated improvement of the contractile function of ischemic/reperfused hearts was examined. Thirty-five-min ischemia/60-min reperfusion recovered little the left ventricular developed pressure (LVDP) and decreased myocardial high-energy phosphates (HEPs). Ischemia induced an accumulation of tissue Na+ content, an increase in cytochrome c in the cytosolic fraction, and a decrease in the oxygen consumption rate (OCR) in perfused hearts. Treatment of the heart with 1 microM diltiazem for the last 3-min of pre-ischemia did not affect the decrease in HEPs during ischemia, whereas that with 3 microM partially attenuated the decrease in ATP, suggesting that 3 microM diltiazem exerted energy-sparing effect. Treatment with 1 microM diltiazem enhanced the post-ischemic recovery of LVDP associated with attenuation of the ischemia-induced accumulation of tissue Na+, increase in cytochrome c in the cytosolic fraction, and decrease in myocardial OCR, and restoration of the myocardial HEPs during reperfusion. Combined treatment with diltiazem and a Na+/H+ exchange inhibitor, but not a Na+ channel blocker, facilitated the attenuation of Na+ accumulation in the ischemic heart and the enhancement of the post-ischemic recovery of LVDP. Sodium lactate, a possible metabolite in ischemic hearts, and sodium chloride increased the Na+ concentration in mitochondria, released cytochrome c into incubation medium, and reduced the mitochondrial respiration. Treatment of isolated mitochondria with diltiazem failed to attenuate the sodium lactate- and sodium chloride-induced alterations. These results suggest that the cardioprotection of diltiazem may be exerted via attenuating cytosolic Na+ overload through Na+ channels in the ischemic heart, leading to preservation of mitochondrial functional ability during ischemia, followed by improvement of post-ischemic energy production and contractile recovery.
研究了D-顺式地尔硫䓬（地尔硫䓬）介导改善缺血/再灌注心脏收缩功能的可能机制。35分钟缺血/60分钟再灌注后，左心室舒张末压（LVDP）恢复甚微，心肌高能磷酸化合物（HEP）减少。缺血导致灌注心脏组织钠含量积聚、细胞溶质部分细胞色素c增加以及氧消耗率（OCR）降低。在缺血前最后3分钟用1微摩尔/升地尔硫䓬处理心脏，并不影响缺血期间HEP的减少，而用3微摩尔/升处理则部分减轻了ATP的减少，表明3微摩尔/升地尔硫䓬发挥了能量节省作用。用1微摩尔/升地尔硫䓬处理可增强缺血后LVDP的恢复，这与减轻缺血诱导的组织钠积聚、细胞溶质部分细胞色素c增加、心肌OCR降低以及再灌注期间心肌HEP的恢复有关。地尔硫䓬与钠/氢交换抑制剂联合处理，但不与钠通道阻滞剂联合处理，可促进缺血心脏中钠积聚的减轻和缺血后LVDP恢复的增强。乳酸钠是缺血心脏中可能的代谢产物，氯化钠可增加线粒体中的钠浓度，将细胞色素c释放到孵育培养基中，并降低线粒体呼吸。用地尔硫䓬处理分离的线粒体未能减轻乳酸钠和氯化钠诱导的变化。这些结果表明，地尔硫䓬的心脏保护作用可能是通过减轻缺血心脏中通过钠通道的细胞溶质钠过载来实现的，从而在缺血期间保留线粒体功能能力，随后改善缺血后能量产生和收缩恢复。
