Department of Biopharmacy, Medical University of Bialystok, Bialystok, Poland.
Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Bialystok, Poland.
J Physiol Pharmacol. 2019 Apr;70(2). doi: 10.26402/jpp.2019.2.02. Epub 2019 Jul 22.
We have recently demonstrated the antithrombotic effect of eplerenone on the arterial thrombotic process in diabetic rats associated with suppression of coagulation and enhancement of fibrinolysis. The aim of this study was to evaluate the role of platelets and endothelium in the mechanism of eplerenone antithrombotic action. Diabetes was induced in male Wistar rats with a single injection of streptozotocin (65 mg/kg). On the 25 day, treatment with eplerenone (100 mg/kg) was initiated for 10 days. Eplerenone did not change hemodynamic parameters (blood pressure, carotid blood flow, and heart rate), however, improved endothelium-dependent vasorelaxation in aortas and small mesenteric arteries, enhanced the aortic amounts of mRNA of endothelial nitric oxide synthase (eNOS), and reduced mRNA of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2. A prolongation of bleeding time and decrease in platelet adhesion to collagen ex vivo was also observed. These changes were accompanied by prolonged time to occlusion and increased blood flow, and finally reduced thrombus mass in diabetic rats. The inhibition of NOS with L-NAME reduced the eplerenone antithrombotic effect. Our study provides evidence that the antithrombotic effect of eplerenone in diabetic rats is nitric oxide-dependent and associated with inhibiting the adhesion of platelets, as well as normalizing endothelial function. The mechanism of eplerenone antithrombotic action in diabetes is a result of improved endothelial nitric oxide bioavailability that leads to the improvement vascular and platelet function.
我们最近证明了依普利酮对伴有凝血抑制和纤溶增强的糖尿病大鼠动脉血栓形成过程的抗血栓作用。本研究的目的是评估血小板和内皮在依普利酮抗血栓作用机制中的作用。雄性 Wistar 大鼠一次性注射链脲佐菌素（65mg/kg）诱导糖尿病。第 25 天，开始用依普利酮（100mg/kg）治疗 10 天。依普利酮不改变血流动力学参数（血压、颈动脉血流量和心率），但改善主动脉和小肠系膜动脉的内皮依赖性血管舒张功能，增加主动脉内皮型一氧化氮合酶（eNOS）的 mRNA 含量，减少烟酰胺腺嘌呤二核苷酸磷酸氢（NADPH）氧化酶 2 的 mRNA 含量。还观察到体外出血时间延长和血小板对胶原的黏附减少。这些变化伴随着糖尿病大鼠的闭塞时间延长、血流量增加和血栓质量减少。NOS 的抑制 L-NAME 降低了依普利酮的抗血栓作用。我们的研究提供了证据，表明依普利酮在糖尿病大鼠中的抗血栓作用是依赖于一氧化氮的，与抑制血小板黏附以及使内皮功能正常化有关。依普利酮在糖尿病中的抗血栓作用机制是改善内皮一氧化氮生物利用度的结果，导致血管和血小板功能的改善。
