Jung Oliver, Albus Udo, Lang Hans-Jochen, Busch Andreas E, Linz Wolfgang
IV. Medical Clinic, Department of Nephrology, J.W. Goethe-University, D-60590 Frankfurt/Main, Germany.
Basic Clin Pharmacol Toxicol. 2004 Jul;95(1):24-30. doi: 10.1111/j.1742-7843.2004.t01-1-pto950105.x.
We investigated the cardioprotective effect of acute and chronic sodium hydrogen exchanger 1 (NHE-1) inhibition with cariporide under pathological conditions in rabbits fed an atherogenic diet (0.25% cholesterol, 3% coconut oil), an experimental model of atherosclerosis. New Zealand White rabbits were fed over 4 weeks with normal diet or with atherogenic diet and randomized in 3 subgroups (n=7 in each group); placebo, acute cariporide (0.3 mg/kg, 10 min. before occlusion of left anterior descending coronary artery and chronic cariporide (4 weeks 0.1% in chow). In the final infarction experiments the animals were subjected to 30 min. of myocardial ischaemia by occlusion of a branch of the left anterior descending coronary artery followed by 2 hr of reperfusion. Infarct mass was evaluated by triphenyl-tetrazolium chloride staining and the infarct size expressed as a percentage of area at risk. Besides the assessment of aortic endothelium-dependent function aortic and cardiac vessels were inspected for atherosclerotic lesions. In cholesterol-fed rabbits, the infarct size was significantly increased when compared with normal diet animals (63+/-3% versus 41+/-3%). Acute cariporide treatment reduced the infarct size in normal diet rabbits to 14%+/-3% (66% decrease, P<0.05) as well as in atherogenic diet rabbits to 22+/-3% (65% decrease, P<0.05). Chronic treatment with cariporide also reduced the infarct size significantly: normal diet 19+/-2% (53% decrease, P<0.05), atherogenic diet 32+/-3% (49% decrease, P<0.05). Total cholesterol serum levels in rabbits with atherogenic diet were significantly higher (15.3+/-2.7 mmol/l) than those on a standard diet (0.65+/-0.08 mmol/l). Chronic cariporide treatment significantly attenuated the increase of serum cholesterol (7.9+/-1.9 mmol/l) and improved the lipoprotein pattern. Although the aortas and heart vessels of hypercholesterolaemic animals were without any histological evidence of atherosclerosis they developed endothelial dysfunction (reduced endothelium-dependent relaxation by ACh), which was prevented by chronic cariporide treatment. Acute and chronic treatment with the NHE-1 inhibitor cariporide significantly reduced infarct mass. This effect was associated with improved endothelial function.
我们研究了在动脉粥样硬化实验模型（喂食含0.25%胆固醇、3%椰子油的致动脉粥样化饮食的兔子）的病理条件下，急性和慢性给予卡立泊来德抑制钠氢交换体1（NHE-1）的心脏保护作用。将新西兰白兔分为两组，分别喂食普通饮食或致动脉粥样化饮食4周，然后随机分为3个亚组（每组n = 7）：安慰剂组、急性卡立泊来德组（0.3 mg/kg，在左冠状动脉前降支闭塞前10分钟给药）和慢性卡立泊来德组（饮食中含0.1%，持续4周）。在最后的梗死实验中，通过闭塞左冠状动脉前降支的一个分支使动物经历30分钟的心肌缺血，随后再灌注2小时。通过氯化三苯基四氮唑染色评估梗死面积，梗死大小以危险区域面积的百分比表示。除了评估主动脉内皮依赖性功能外，还检查主动脉和心脏血管的动脉粥样硬化病变。与喂食普通饮食的动物相比，喂食胆固醇的兔子梗死面积显著增加（63±3%对41±3%）。急性给予卡立泊来德可使喂食普通饮食的兔子梗死面积降至14%±3%（减少66%，P<0.05），使喂食致动脉粥样化饮食的兔子梗死面积降至22%±3%（减少65%，P<0.05）。慢性给予卡立泊来德也显著降低了梗死面积：喂食普通饮食的兔子为19%±2%（减少53%，P<0.05），喂食致动脉粥样化饮食的兔子为32%±3%（减少49% P<0.05）。喂食致动脉粥样化饮食的兔子血清总胆固醇水平（15.3±2.7 mmol/l）显著高于喂食标准饮食的兔子（0.65±0.08 mmol/l）。慢性给予卡立泊来德显著减轻了血清胆固醇的升高（7.9±1.9 mmol/l）并改善了脂蛋白模式。尽管高胆固醇血症动物的主动脉和心脏血管没有任何动脉粥样硬化的组织学证据，但它们出现了内皮功能障碍（乙酰胆碱介导的内皮依赖性舒张减弱），而慢性给予卡立泊来德可预防这种情况。急性和慢性给予NHE-1抑制剂卡立泊来德均显著减少了梗死面积。这种作用与内皮功能改善有关。
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