Lee Tsung-Ming, Lin Mei-Shu, Chou Tsai-Fwu, Tsai Chang-Her, Chang Nen-Chung
Cardiology Section, Department of Internal Medicine, Chi-Mei, Medical Center, Taipei Medical University, 901 Chung-Hwa Road, Yang-Kan City, Tainan 710, Taiwan.
Atherosclerosis. 2004 Oct;176(2):273-8. doi: 10.1016/j.atherosclerosis.2004.06.005.
Epidemiological studies showed that hypercholesterolemia was associated with a higher left ventricular mass. Myocardial ATP-sensitive potassium (K(ATP)) channels have been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on hypercholesterolemia-induced ventricular hypertrophy and whether the attenuated hypertrophic effect was via activation of myocardial K(ATP) channels. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to pravastatin in cholesterol-fed (1%) rabbits. Male New Zealand White rabbits were randomized to either vehicle, nicorandil (an agonist of K(ATP) channels), pravastatin, glibenclamide (an antagonist of K(ATP) channels), or a combination of nicorandil and glibenclamide or pravastatin and glibenclamide for 8 weeks. The left ventricular weight and left ventricular myocyte sizes increased 8 weeks after cholesterol-feeding in comparison to that in normocholesterolemic rabbits. Pravastatin administration significantly decreased the left ventricular weight by 12% and cardiomyocyte cell areas by 30%. Hyperlipidemic rabbits in the nicorandil- and pravastatin-treated groups significantly attenuated cardiomyocyte hypertrophy, as compared with the vehicle-treated group (3162 +/- 277 microm(2), 3372 +/- 228 microm(2) versus 4388 +/- 163 microm(2) in the vehicle group, both P < 0.0001, respectively). Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating K(ATP) channels as the relevant target. The results of the present study suggest a pathogenetic role of K(ATP) channels in hypercholesterolemia-induced ventricular hypertrophy. The antihypertropic effects of pravastatin may be related to activation of K(ATP) channels, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.
流行病学研究表明，高胆固醇血症与左心室质量增加有关。心肌ATP敏感性钾（K(ATP)）通道与心脏肥大的发生有关。我们研究了普伐他汀对高胆固醇血症诱导的心室肥大的影响，以及这种减轻肥大的作用是否通过激活心肌K(ATP)通道实现。在本研究中，我们评估了胆固醇喂养（1%）兔对普伐他汀的血流动力学、生化和形态学反应。雄性新西兰白兔被随机分为给予溶剂、尼可地尔（K(ATP)通道激动剂）、普伐他汀、格列本脲（K(ATP)通道拮抗剂），或尼可地尔与格列本脲联合用药、普伐他汀与格列本脲联合用药，持续8周。与正常胆固醇血症兔相比，胆固醇喂养8周后左心室重量和左心室心肌细胞大小增加。给予普伐他汀可使左心室重量显著降低12%，心肌细胞面积显著减少30%。与溶剂处理组相比，尼可地尔和普伐他汀治疗组的高脂血症兔心肌细胞肥大明显减轻（溶剂组为4388±163μm²，尼可地尔组为3162±277μm²，普伐他汀组为3372±228μm²，两组P均<0.0001）。给予格列本脲可消除尼可地尔诱导的效应。同样，加入格列本脲可逆转普伐他汀诱导的有益效应，提示K(ATP)通道是相关靶点。本研究结果表明K(ATP)通道在高胆固醇血症诱导的心室肥大中起致病作用。普伐他汀的抗肥大作用可能与激活K(ATP)通道有关，并通过致动脉粥样硬化饮食改善心肌细胞肥大的发展。
