Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
Life Sci. 2010 Feb 27;86(9-10):322-30. doi: 10.1016/j.lfs.2009.12.013. Epub 2010 Jan 7.
Recurrent hypoxia due to sleep apnea syndrome is implicated in cardiovascular events, especially in diabetic patients, but the underlying mechanisms remain controversial. We previously reported that angiotensin II receptor blockers can improve hypoxia-induced left ventricular remodeling. The aim of this study was to examine the effect on left ventricular remodeling of adding a calcium channel blocker to angiotensin II receptor blocker therapy in diabetic mice exposed to recurrent hypoxia.
Male db/db mice (8-week-old) and age-matched control db/+ mice were fed a Western diet and subjected to recurrent hypoxia (oxygen at 10+/-0.5% for 8h daily during the daytime) or normoxia for 3weeks. Hypoxic db/db mice were treated with the vehicle, olmesartan (3mg/kg/day), nifedipine (10mg/kg/day), or both drugs.
Recurrent hypoxia caused hypertrophy of cardiomyocytes, interstitial fibrosis, and a significant increase in expression of the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in the left ventricular myocardium. Treatment with olmesartan, nifedipine, or both drugs had no effect on systolic blood pressure, and each treatment achieved similar suppression of 4-HNE expression. Olmesartan and the combination with olmesartan and nifedipine significantly prevented cardiomyocyte hypertrophy more than treatment with nifedipine alone. On the other hand, olmesartan combined with nifedipine significantly reduced cytokine expression, superoxide production and matrix metalloproteinase (MMP)-9 activity, and significantly suppressed interstitial fibrosis in the left ventricular myocardium.
The combination with olmesartan and nifedipine, as well as a monotherapy with olmesartan, exerts preferable cardioprotection in diabetic mice exposed to recurrent hypoxia.
睡眠呼吸暂停综合征引起的反复缺氧与心血管事件有关，尤其是在糖尿病患者中，但潜在机制仍存在争议。我们之前报道过血管紧张素 II 受体阻滞剂可以改善缺氧引起的左心室重构。本研究旨在探讨在反复缺氧的糖尿病小鼠中，在血管紧张素 II 受体阻滞剂治疗的基础上加用钙通道阻滞剂对左心室重构的影响。
雄性 db/db 小鼠（8 周龄）和年龄匹配的对照 db/+ 小鼠给予西方饮食，并接受反复缺氧（白天每天 8 小时氧浓度为 10+/-0.5%）或常氧 3 周。缺氧 db/db 小鼠给予载体、奥美沙坦（3mg/kg/天）、硝苯地平（10mg/kg/天）或两药联合治疗。
反复缺氧导致心肌细胞肥大、间质纤维化，并显著增加左心室心肌中氧化应激标志物 4-羟基-2-壬烯醛（4-HNE）的表达。奥美沙坦、硝苯地平或两药联合治疗对收缩压均无影响，每种治疗均能达到类似的 4-HNE 表达抑制。奥美沙坦联合硝苯地平治疗比单独使用硝苯地平治疗更显著地预防心肌细胞肥大。另一方面，奥美沙坦联合硝苯地平治疗显著降低了左心室心肌中的细胞因子表达、超氧化物产生和基质金属蛋白酶（MMP）-9 活性，并显著抑制间质纤维化。
奥美沙坦联合硝苯地平以及奥美沙坦单药治疗均可在反复缺氧的糖尿病小鼠中发挥更好的心脏保护作用。
