a Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut 11-0236, Lebanon.
Can J Physiol Pharmacol. 2013 Oct;91(10):830-8. doi: 10.1139/cjpp-2013-0095. Epub 2013 Jun 3.
This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [(125)I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K-n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.
本研究聚焦于在 1 型糖尿病大鼠模型中，在冠状动脉内皮细胞和心肌细胞水平上，阿利克仑和（或）胰高血糖素样肽-1 类似物对内皮素-1（ET-1）与其受体亚型 A（ETAR）和 B（ETBR）结合亲和力/调节的影响。使用了七组：（i）正常大鼠，（ii）诱导糖尿病大鼠，（iii）用胰岛素治疗的诱导糖尿病大鼠，（iv）用 exendin-4 治疗的诱导糖尿病大鼠，（v）用阿利克仑治疗的诱导糖尿病大鼠，（vi）用胰岛素加阿利克仑共同治疗的诱导糖尿病大鼠，和（vii）用 exendin-4 加阿利克仑共同治疗的诱导糖尿病大鼠。通过心内灌注[（125）I]-ET-1 来评估 ET-1 与 ETAR 和 ETBR 的结合亲和力（τ = 1/K-n），分别在冠状动脉内皮细胞和心肌细胞水平上进行。使用酶免疫测定法测量血浆 ET-1 水平，而使用 Western blot 检测 ETAR 和 ETBR 的密度。在心肌细胞和冠状动脉内皮细胞中，正常大鼠和糖尿病大鼠之间的 ETAR 和 ETBR 的 τ 值没有显著差异。exendin-4 使冠状动脉内皮细胞上的 ETAR 和 ETBR 的 τ 值正常化，而阿利克仑使心肌细胞上的 ETAR 和 ETBR 的 τ 值正常化。此外，与糖尿病动物中上调的 ETAR 和下调的 ETBR 带密度相比，阿利克仑和 exendin-4 的单一治疗可使 ETAR 和 ETBR 的密度正常化。我们的数据表明，阿利克仑减轻了 1 型糖尿病中与糖尿病相关的肥大。
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