Hoshida S, Yamashita N, Igarashi J, Aoki K, Kuzuya T, Hori M
First Department of Medicine, Osaka University Medical School, Japan.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2801-7. doi: 10.1161/01.atv.17.11.2801.
We previously reported that administration of NO donors ameliorates the severity of myocardial injury in cholesterol-fed rabbits. We now evaluated the effects of probucol, a lipid-lowering antioxidant that can preserve endothelium-dependent relaxation (EDR), in the aortas of cholesterol-fed rabbits. We examined the effects of short-term (7 days) or long-term (24 weeks) administration of 1% probucol on the size of infarcts resulting from 30 minutes of coronary occlusion followed by reperfusion (for 48 hours) in Watanabe heritable hyperlipidemic (WHHL) rabbits. Infarcts in untreated WHHL rabbits were significantly larger than those in the rabbits receiving the long-term but not the short-term treatment with probucol (72.2 +/- 5.4%, 37.6 +/- 6.4%, and 66.7 +/- 3.5%, respectively). Long-term probucol treatment also significantly reduced myeloperoxidase activity in both ischemic and nonischemic myocardium and suppressed P-selectin expression in the coronary vasculature. No significant differences were observed in hemodynamic parameters during myocardial ischemia/reperfusion. Long-term probucol treatment significantly reduced the surface area of atherosclerotic plaque lesions in the aorta (24.4 +/- 3.8% vs 46.3 +/- 6.3, P < .05). Moreover, long-term probucol treatment restored acetylcholine-induced EDR in aortic rings but did not affect sodium nitroprusside-induced relaxation. Finally, long-term probucol treatment resulted in significantly elevated cGMP levels in the aorta. These results indicate that long-term probucol treatment significantly ameliorates myocardial injury in heritable atherosclerotic rabbits, perhaps by reducing the accumulation of leukocytes in the myocardium and atherosclerotic vascular lesions. Thus, long-term administration appears to suppress the progression of atherosclerotic vascular disease in this animal model.
我们之前报道过，给予一氧化氮供体可减轻胆固醇喂养兔的心肌损伤严重程度。我们现在评估了普罗布考（一种可维持内皮依赖性舒张功能（EDR）的降脂抗氧化剂）对胆固醇喂养兔主动脉的影响。我们研究了在渡边遗传性高脂血症（WHHL）兔中，短期（7天）或长期（24周）给予1%普罗布考对冠状动脉闭塞30分钟后再灌注（48小时）所导致梗死面积的影响。未治疗的WHHL兔的梗死面积显著大于接受长期而非短期普罗布考治疗的兔（分别为72.2±5.4%、37.6±6.4%和66.7±3.5%）。长期普罗布考治疗还显著降低了缺血和非缺血心肌中的髓过氧化物酶活性，并抑制了冠状动脉血管中P-选择素的表达。在心肌缺血/再灌注期间，血流动力学参数未观察到显著差异。长期普罗布考治疗显著减小了主动脉粥样硬化斑块病变的表面积（24.4±3.8%对46.3±6.3，P<0.05）。此外，长期普罗布考治疗恢复了主动脉环中乙酰胆碱诱导的EDR，但不影响硝普钠诱导的舒张。最后，长期普罗布考治疗导致主动脉中cGMP水平显著升高。这些结果表明，长期普罗布考治疗可显著减轻遗传性动脉粥样硬化兔的心肌损伤，可能是通过减少心肌中白细胞的积聚和动脉粥样硬化血管病变。因此，长期给药似乎可抑制该动物模型中动脉粥样硬化血管疾病的进展。
