阿托伐他汀和氯沙坦低剂量联合直接改善离体大鼠主动脉环舒张功能，减轻缺血再灌注损伤。
A low-dose atorvastatin and losartan combination directly improves aortic ring relaxation and diminishes ischaemic-reperfusion injury in isolated rat hearts.
机构信息
Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
出版信息
Med Sci Monit. 2012 Sep;18(9):BR366-74. doi: 10.12659/msm.883347.
BACKGROUND
The cardiovascular pleiotropic effects of statins and angiotensin receptor blockers (ARBs) could be of interest for innovative preventive approaches. We aimed to investigate whether low-dose atorvastatin and losartan, separately not possessing protective cardiovascular pleiotropic effects, express them when combined.
MATERIAL/METHODS: Forty-five adult male Wistar rats were anaesthetized and their thoracic aortas and hearts were isolated. Relaxation of aortic rings, coronary flow rate and the extent of myocardial ischaemic-reperfusion injury were measured. Different concentrations (0.01, 0.1, 1.0 µM) of atorvastatin and losartan added to a perfusion medium were first tested. The separate drugs, which were ineffective, were then combined at the same concentrations and the concentration was tested in the same model.
RESULTS
Low concentrations of atorvastatin or losartan (0.1 and 1 µM, respectively) produced no effects in isolated aorta. However, surprisingly, when these drug concentrations were combined, a significantly improved endothelium-dependent relaxation of the thoracic aorta was observed. Similarly, when combining individually ineffective concentrations of atorvastatin or losartan (0.01 and 0.1 µM, respectively), significantly increased coronary flow and a decreased extent of myocardial injury were observed. By using a nitric oxide-synthase inhibitor, we demonstrated that the vasodilatory effects obtained were nitric oxide-dependent. The degree of effectiveness by the combination was comparable to that obtained by 10-fold (atorvastatin) or 100-fold (losartan) higher concentrations of the separate drugs.
CONCLUSIONS
Our results revealed that remarkable additive/synergistic effects exist between low-doses of a statin (atorvastatin) and an ARB (losartan), resulting in important cardiovascular protection. This new concept could be valuable in cardiovascular prevention.
背景
他汀类药物和血管紧张素受体阻滞剂（ARB）的心血管多效作用可能是创新预防方法的关注点。我们旨在研究低剂量阿托伐他汀和氯沙坦是否在联合使用时表现出这些保护心血管的多效作用，而它们单独使用时并不具有这些作用。
材料/方法：将 45 只成年雄性 Wistar 大鼠麻醉，并分离其胸主动脉和心脏。测量主动脉环的松弛度、冠状动脉流量和心肌缺血再灌注损伤的程度。首先测试阿托伐他汀和氯沙坦在灌注介质中的不同浓度（0.01、0.1、1.0 μM）。然后将单独使用无效的药物以相同浓度组合，并在相同模型中测试该浓度。
结果
低浓度的阿托伐他汀或氯沙坦（分别为 0.1 和 1 μM）对离体主动脉没有作用。然而，令人惊讶的是，当这些药物浓度组合使用时，观察到胸主动脉的内皮依赖性松弛显著改善。同样，当组合使用单独无效浓度的阿托伐他汀或氯沙坦（分别为 0.01 和 0.1 μM）时，观察到冠状动脉流量显著增加，心肌损伤程度降低。通过使用一氧化氮合酶抑制剂，我们证明了所获得的血管舒张作用是依赖于一氧化氮的。组合的效果程度与单独使用 10 倍（阿托伐他汀）或 100 倍（氯沙坦）更高浓度的药物所获得的效果相当。
结论
我们的结果表明，他汀类药物（阿托伐他汀）和 ARB（氯沙坦）的低剂量之间存在显著的相加/协同作用，从而导致重要的心血管保护。这一新概念在心血管预防中可能具有重要价值。
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