Hoque A N, Haist J V, Karmazyn M
Department of Pharmacology & Toxicology, Faculty of Medicine, University of Western Ontario, London, Canada.
Circ Res. 1997 Jan;80(1):95-102. doi: 10.1161/01.res.80.1.95.
Lysophophatidylcholine (LysoPC) accumulates rapidly in the ischemic myocardium and is an important mediator of ischemia-induced cell injury. Na(+)-H+ exchange (NHE) inhibition has been demonstrated to protect the ischemic and reperfused myocardium. We determined whether NHE inhibition can also modulate cardiotoxicity produced by LysoPC (3 and 5 mumol/L) in isolated rat hearts. At 3 mumol/L, LysoPC produced a depression in left ventricular developed pressure (LVDP) and elevation in left ventricular end-diastolic pressure (LVEDP), which were 19 +/- 7% and 1290 +/- 205% of pre-LysoPC values, respectively, after 30 minutes of treatment. In the presence of the NHE inhibitor 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate (HOE 642, 5 mumol/L), LVDP was reduced to only 80.8 +/- 8.6%, and LVEDP increased to 270 +/- 32% (P < .05 for both parameters). LysoPC significantly depressed tissue ATP, creatine phosphate, and glycogen contents and increased lactate levels, all of which were significantly attenuated by HOE 642. Moreover, marked LysoPC-induced ultrastructural abnormalities, including mitochondrial and myofibrillar disruption, were totally prevented by HOE 642. This protection was mimicked by another NHE inhibitor, methylisobutylamiloride (5 mumol/L). HOE 642 was also effective against injury produced by 5 mumol/L LysoPC although, generally, the protection was less marked than that observed against 3 mumol/L; LVDP depression after 30 minutes was 10.1 +/- 4.3% and 41.4 +/- 10.4% of pre-LysoPC values in control and HOE 642-treated hearts, respectively (P < .05), whereas corresponding LVEDP elevations were 1629 +/- 393% and 990 +/- 144% (P > .05). In myocytes superfused with bicarbonate-free buffer subjected to acid loading by NH4Cl pulsing, pH recovery (as measured by acid flux) was significantly stimulated by 3 mumol/L LysoPC, indicative of NHE activation. Our study shows that cardiac injury produced by low concentrations of LysoPC can be effectively attenuated by NHE inhibition. The results also suggest that the beneficial effects of NHE inhibitors on the ischemic myocardium may be, at least partially, mediated by inhibiting the deleterious effects of LysoPC.
溶血磷脂酰胆碱（LysoPC）在缺血心肌中迅速蓄积，是缺血诱导的细胞损伤的重要介质。已证实抑制钠氢交换（NHE）可保护缺血及再灌注心肌。我们研究了抑制NHE是否也能调节LysoPC（3和5μmol/L）对离体大鼠心脏产生的心脏毒性。在3μmol/L时，LysoPC使左心室舒张末压（LVDP）降低，左心室舒张末压（LVEDP）升高，处理30分钟后，分别为LysoPC处理前值的19±7%和1290±205%。在NHE抑制剂4-异丙基-3-甲基磺酰基苯甲酰胍甲磺酸盐（HOE 642，5μmol/L）存在的情况下，LVDP仅降至80.8±8.6%，LVEDP升至270±32%（两个参数P均<0.05）。LysoPC显著降低组织ATP、磷酸肌酸和糖原含量，并增加乳酸水平，而HOE 642均使其显著减轻。此外，HOE 642完全防止了LysoPC诱导的明显超微结构异常，包括线粒体和肌原纤维破坏。另一种NHE抑制剂甲基异丁基阿米洛利（5μmol/L）也具有类似的保护作用。HOE 642对5μmol/L LysoPC产生的损伤也有效，尽管总体上其保护作用不如对3μmol/L时明显；处理30分钟后，对照心脏和HOE 642处理心脏的LVDP降低分别为LysoPC处理前值的10.1±4.3%和41.4±10.4%（P<0.05），而相应的LVEDP升高分别为1629±393%和990±144%（P>0.05）。在无碳酸氢盐缓冲液中灌流并用氯化铵脉冲进行酸负荷处理的心肌细胞中，3μmol/L LysoPC显著刺激pH恢复（通过酸通量测量），表明NHE激活。我们的研究表明，抑制NHE可有效减轻低浓度LysoPC产生的心脏损伤。结果还提示，NHE抑制剂对缺血心肌的有益作用可能至少部分是通过抑制LysoPC的有害作用介导的。
