Crespo María J, Quidgley José
María J Crespo, Departments of Physiology and Anesthesiology, University of Puerto Rico-School of Medicine, San Juan, PR 00936-5067, United States.
World J Diabetes. 2015 Aug 25;6(10):1168-78. doi: 10.4239/wjd.v6.i10.1168.
To investigate if the effect of statins improving cardiovascular (CV) status of diabetics is drug-specific or class-dependent, and the underlying mechanisms involved.
We compared the results of daily administration over a four-week period of a low dose (10 mg/kg per day) of atorvastatin (AV), simvastatin (SV), and pravastatin (PV) on cardiac performance in diabetic rats. Echocardiographic variables were tested, as well as systolic blood pressure (SBP), acetylcholine (ACh)-induced relaxation, plasma cholesterol levels, and perivascular fibrosis. Malondialdehyde (MDA) and 4-hydroxyalkenal (4-HAE), and endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) protein levels were also measured in cardiac and aortic homogenates.
In untreated diabetic rats, cholesterol levels were higher than in control rats (CT; n = 8, P < 0.05), and the low dose of statins used did not modify these levels. In diabetic rats, SBP was higher than in CT, and was significantly reduced by all three statins (n = 10, P < 0.05). Echocardiographic parameters (EF, SV, and COI) were all lower in untreated diabetic rats than in CT (n = 10, P < 0.05). These CV parameters were equally improved by all three statins. The maximal relaxation (EMax) induced by ACh in aortic ring from diabetic rats was also improved. Moreover, this relaxation was abolished by 1 mmol/L NG-nitro-L-arginine methyl ester, suggesting the involvement of a NO-dependent mechanism.
AV, SV, and PV are equally effective in improving CV performance in diabetic rats. All tree statins decreased media thickness, perivascular fibrosis, and both MDA and 4-HAE in the aortas of diabetic rats, without affecting eNOS and iNOS protein levels. The observed hemodynamic benefits are cholesterol-independent. These benefits appear to be secondary to the improved endothelial function, and to the reduced vascular tone and remodeling that result from decreased oxidative stress.
研究他汀类药物改善糖尿病患者心血管（CV）状况的作用是药物特异性的还是类别依赖性的，以及其中涉及的潜在机制。
我们比较了低剂量（每天10毫克/千克）阿托伐他汀（AV）、辛伐他汀（SV）和普伐他汀（PV）在四周内每日给药对糖尿病大鼠心脏功能的影响。测试了超声心动图变量，以及收缩压（SBP）、乙酰胆碱（ACh）诱导的舒张、血浆胆固醇水平和血管周围纤维化。还测量了心脏和主动脉匀浆中的丙二醛（MDA）和4-羟基烯醛（4-HAE），以及内皮型一氧化氮合酶（eNOS）和诱导型一氧化氮合酶（iNOS）蛋白水平。
在未经治疗的糖尿病大鼠中，胆固醇水平高于对照大鼠（CT；n = 8，P < 0.05），所用低剂量他汀类药物未改变这些水平。在糖尿病大鼠中，SBP高于CT，并且所有三种他汀类药物均使其显著降低（n = 10，P < 0.05）。未经治疗的糖尿病大鼠的超声心动图参数（EF、SV和COI）均低于CT（n = 10，P < 0.05）。所有三种他汀类药物对这些心血管参数的改善程度相同。糖尿病大鼠主动脉环中ACh诱导的最大舒张（EMax）也得到改善。此外，1毫摩尔/升NG-硝基-L-精氨酸甲酯可消除这种舒张，提示涉及NO依赖性机制。
AV、SV和PV在改善糖尿病大鼠心血管功能方面同样有效。所有三种他汀类药物均降低了糖尿病大鼠主动脉的中层厚度、血管周围纤维化以及MDA和4-HAE，而不影响eNOS和iNOS蛋白水平。观察到的血流动力学益处与胆固醇无关。这些益处似乎继发于内皮功能的改善以及氧化应激降低导致的血管张力和重塑的减轻。
