Department of Pharmacology, Ankara University, Ankara, Turkey.
Br J Pharmacol. 2020 Dec;177(24):5580-5594. doi: 10.1111/bph.15269. Epub 2020 Nov 15.
Carvedilol is a third-generation β-adrenoceptor antagonist, which also stimulates β-arrestins. β-arrestins initiate intracellular signalling and are involved in insulin release and sensitivity. Carvedilol is superior in effectiveness to other drugs that are used for similar indications and does not cause insulin resistance or diabetes, which can occur with other β-antagonists. We have shown that carvedilol increased glucose usage in C2C12 cells. We investigate the biased agonist efficacy of carvedilol on β-arrestins.
Streptozotocin (STZ)-induced diabetes rat model was used to induce metabolic and cardiac disorders. After 8 weeks of diabetes, animals were treated with carvedilol or vehicle for another 4 weeks. In vitro heart function was evaluated at baseline as well as with increasing concentrations of isoprenaline. Effects of diabetes and carvedilol treatment on β-arrestins, ERK, PPARα, CD36 proteins and pyruvate kinase activity were evaluated. β-arrestins were silenced in C2C12 cells by using siRNA. Acute effects of carvedilol on ERK, CD36, mitochondrial transcription factor A, cardiolipin proteins and citrate synthase activity were investigated.
Carvedilol reversed the deterioration of cardiac function in diabetes and diabetes-induced decrease in β-arrestins in rats. Carvedilol decreased the expression of CD36 in diabetes and increased mitochondrial transcription factor A and cardiolipin proteins. Silencing of β-arrestins in cells prevented the effects of carvedilol on these proteins.
The metabolic effects of carvedilol seem to be related to biased activation of β-arrestins. Patients with cardiovascular and metabolic disorders may benefit from new compounds that selectively act on β-arrestins.
卡维地洛是第三代β肾上腺素受体拮抗剂，同时也能刺激β-arrestin。β-arrestin 启动细胞内信号转导，并参与胰岛素的释放和敏感性。卡维地洛在疗效上优于其他用于类似适应症的药物，并且不会引起胰岛素抵抗或糖尿病，而其他β拮抗剂则可能会引起这些问题。我们已经表明，卡维地洛可增加 C2C12 细胞中的葡萄糖利用率。我们研究了卡维地洛对β-arrestin 的偏向激动剂效力。
使用链脲佐菌素（STZ）诱导的糖尿病大鼠模型诱导代谢和心脏紊乱。糖尿病 8 周后，动物用卡维地洛或载体再治疗 4 周。在基础状态以及异丙肾上腺素浓度增加时，评估体外心脏功能。评估糖尿病和卡维地洛治疗对β-arrestin、ERK、PPARα、CD36 蛋白和丙酮酸激酶活性的影响。使用 siRNA 沉默 C2C12 细胞中的β-arrestin。研究卡维地洛对 ERK、CD36、线粒体转录因子 A、心磷脂蛋白和柠檬酸合酶活性的急性影响。
卡维地洛逆转了糖尿病大鼠心脏功能的恶化和糖尿病引起的β-arrestin 减少。卡维地洛降低了糖尿病中 CD36 的表达，并增加了线粒体转录因子 A 和心磷脂蛋白。细胞中β-arrestin 的沉默阻止了卡维地洛对这些蛋白的作用。
卡维地洛的代谢作用似乎与β-arrestin 的偏向激活有关。患有心血管和代谢紊乱的患者可能会受益于选择性作用于β-arrestin 的新型化合物。
