Department of Cardiology, Division of Pharmacology, Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
Am J Physiol Heart Circ Physiol. 2012 Jan 1;302(1):H85-94. doi: 10.1152/ajpheart.00311.2011. Epub 2011 Oct 7.
Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.
在糖尿病（DM）相关冠状动脉疾病（CAD）发展早期，对患者的冠状动脉功能进行详细评估较为困难。因此，我们研究了具有 2 型特征的动脉粥样硬化前 DM 猪模型中的冠状动脉管腔和小动脉功能。与 SFC 和标准（对照）饮食上的对照猪相比，用链脲佐菌素诱导的 SFC 加 DM 猪表现出与 DM 相关的代谢改变和主动脉的早期动脉粥样硬化发展。评估了 SFC + DM 猪的内皮依赖性血管舒张对缓激肽（BK）的作用，包括或不包括一氧化氮（NO）合酶阻断，内皮非依赖性血管舒张对外源性 NO 供体（S-亚硝基-N-乙酰青霉胺）的作用，以及内皮素（ET）-1 收缩作用及其受体亚型阻断。在体外进行了研究。小冠状动脉，而不是管腔血管，表现出功能改变，包括由于 NO 丧失导致 BK 诱导的血管舒张受损（与 SFC 和对照相比，P < 0.01），以及由于 ET(A)受体优势降低导致 ET-1 收缩作用减弱（与 SFC 和对照相比，P < 0.01）。其他血管运动反应未改变。总之，该模型在 DM 中动脉粥样硬化的早期过程中显示出与 NO 和 ET-1 系统相关的特定冠状动脉微血管改变。特别是，改变的 ET-1 系统与致动脉粥样硬化条件下的高血糖相关，强调了该系统在 DM 相关 CAD 发展中的重要性。
