Marano Giuseppe, Vergari Alessandro, Catalano Liviana, Gaudi Simona, Palazzesi Sergio, Musumeci Marco, Stati Tonino, Ferrari Alberto U
Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy.
Br J Pharmacol. 2004 Feb;141(3):526-32. doi: 10.1038/sj.bjp.0705631. Epub 2004 Jan 12.
Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631
心肌肥厚是对后负荷升高的一种稳态反应。钠氢交换体（NHE）抑制可减轻左心室肥厚（LVH）和心肌梗死动物模型中的肥厚反应。我们研究了在压力超负荷条件下，用卡立泊来德（一种选择性钠氢交换体同工型1（NHE-1）抑制剂）进行长期治疗对左心室（LV）收缩和舒张功能的影响。将雄性CD-1小鼠随机分为两组，一组给予对照饮食，另一组给予添加了6000 ppm卡立泊来德的相同饮食。通过胸主动脉缩窄诱导心脏压力超负荷。在假手术组和缩窄组小鼠术后2周和5周，通过超声心动图和心导管检查评估左心室大小、收缩和舒张功能。还进行了组织学分析。压力超负荷2周后，给予赋形剂处理的缩窄组小鼠（Veh-Bd）左心室重量标准化增加（约+50%），心室大小和功能正常，而给予卡立泊来德处理的缩窄组小鼠（Car-Bd）尽管左心室肥厚明显减轻，但收缩力和收缩功能得以保留。各组间舒张功能无显著差异。5周后，Veh-Bd出现左心室腔扩大和收缩功能障碍，表现为左心室舒张末期直径增加16%、心肌收缩力降低36%、缩短分数百分比降低26%。相比之下，Car-Bd显示左心室质量增加减弱、心室大小正常且收缩功能维持。一个明显的组织学特征是，在缩窄组小鼠中，卡立泊来德减轻了心肌细胞肥大的发展，但未减轻随之而来的心肌纤维化。总之，本研究结果表明：（i）对压力超负荷的肥厚反应依赖于NHE-1活性；（ii）在5周阶段，NHE-1抑制可防止缩窄诱导的左心室功能恶化。《英国药理学杂志》（2004年）141卷，526 - 532页。doi:10.1038/sj.bjp.0705631
