Carvedilol is a non-selective antagonist of α1 and β-adrenergic receptors (ARs) [1]. Adrenergic receptors are a type of G protein-coupled receptors and are the targets for adrenaline and noradrenaline in the sympathetic nervous system [2]. Carvedilol is a multi-purpose antihypertensive agent that can be used to treat congestive heart failure (CHF) and hypertension [3]. Carvedilol is also an autophagy inducer that can inhibit the NLRP3 inflammatory body [4].
In vitro, pre-treatment with Carvedilol (5μM; 18h) can inhibit the quantity and activity of MMP-2 and 9 in human aortic smooth muscle cells (HASMCs) stimulated by TNF-α [5]. Pre-treatment with Carvedilol (1-100μM; 48h) 30 minutes before lipopolysaccharide (LPS) stimulation can inhibit lipid peroxidation and IL-1β production in U937 cells in a dose-dependent manner [6].
In vivo, oral administration of Carvedilol (20mg/kg/day for 3 weeks) significantly reduced the severity of experimental autoimmune myocarditis (EAM) in rats with myocarditis and inhibited the thickening of the left ventricular posterior wall and the mRNA expression of inflammatory cytokines and IL-1β protein in myocarditis, as well as the content of myocardial protein carbonylation and peroxide acidic reaction products [6]. Carvedilol (5, 10mg/kg/day for 6 weeks; gavage) treatment significantly reduced the expression of α-SMA, CD31, CD34 and VWF in carbon tetrachloride-induced fibrotic mice, while also reducing serum levels of MMP-8, VEGF and angiopoietin-2 [7].
References:
[1] Yue T L, Cheng H Y, Lysko P G, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger[J]. Journal of Pharmacology and Experimental Therapeutics, 1992, 263(1): 92-98.
[2] Furchgott R F. The receptors for epinephrine and norepinephrine (adrenergic receptors)[J]. Pharmacological reviews, 1959, 11(2): 429-441.
[3] Feuerstein GZ, et al. Myocardial protection by the novel vasodilating beta-blocker, carvedilol: potential relevance of anti-oxidant activity. J Hypertens Suppl. 1993 Jun;11(4):S41-8.
[4] Wong WT, et al. Repositioning of the β-Blocker Carvedilol as a Novel Autophagy Inducer That Inhibits the NLRP3 Inflammasome. Front Immunol. 2018 Aug 22;9:1920.
[5] Wu TC, Chen YH, Leu HB, et al. Carvedilol, a pharmacological antioxidant, inhibits neointimal matrix metalloproteinase-2 and -9 in experimental atherosclerosis. Free Radic Biol Med. 2007;43(11):1508-1522.
[6] Yuan Z, Shioji K, Kihara Y, et al. Cardioprotective effects of carvedilol on acute autoimmune myocarditis: anti-inflammatory effects associated with antioxidant property[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2004, 286(1): H83-H90.
[7] Wu Y, Li Z, Xiu A Y, et al. Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice[J]. Drug design, development and therapy, 2019: 2667-2676.
Carvedilol是一种非选择性α1和β-肾上腺素能受体（Ars）的拮抗剂 [1]。肾上腺素能受体是一类G蛋白偶联受体，是参与交感神经系统的肾上腺素和肾上腺素的靶点 [2]。Carvedilol是一种多用途降压剂，可用于治疗充血性心衰竭（CHF）和高血压[3]。Carvedilol也是一种自噬（autophagy）诱导剂，可抑制NLRP3炎性小体 [4]。
在体外，Carvedilol（5μM; 18h）预处理能够抑制TNF-α刺激的人主动脉平滑肌细胞（HASMCs）中MMP-2和9的数量和活性 [5]。在脂多糖（LPS）刺激前30min用Carvedilol（1-100μM; 48h）预处理能够以剂量依赖性方式抑制U937细胞的脂质过氧化和IL-1β的生成[6]。
在体内，Carvedilol（20mg/kg/day for 3 weeks）通过口服治疗显著降低了实验性自身免疫性心肌炎（EAM）大鼠心肌炎的严重程度，并抑制了左心室后壁的增厚和心肌炎中炎症细胞因子与IL-1β蛋白的mRNA表达，降低了心肌蛋白羰基含量和心肌过氧化物酸性反应产物 [6]。Carvedilol（5, 10mg/kg/day for 6 weeks; gavage）治疗显著降低了四氯化碳诱导的纤维化小鼠α-SMA、CD31、CD34和VWF表达，同时降低了血清MMP-8、VEGF和血管生成素-2水平 [7]。