Schwarz Rebecca, Hofmann Britt, Gergs Ulrich, Neumann Joachim
Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Department of Cardiac Surgery, Mid-German Heart Center, University Hospital Halle, Halle (Saale), Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Apr;397(4):2183-2202. doi: 10.1007/s00210-023-02747-4. Epub 2023 Oct 6.
Carbachol, an agonist at muscarinic receptors, exerts a negative inotropic effect in human atrium. Carbachol can activate protein phosphatases (PP1 or PP2A). We hypothesized that cantharidin or sodium fluoride, inhibitors of PP1 and PP2A, may attenuate a negative inotropic effect of carbachol. During bypass-surgery trabeculae carneae of human atrial preparations (HAP) were obtained. These trabeculae were mounted in organ baths and electrically stimulated (1 Hz). Force of contraction was measured under isometric conditions. For comparison, we studied isolated electrically stimulated left atrial preparations (LA) from mice. Cantharidin (100 µM) and sodium fluoride (3 mM) increased force of contraction in LA (n = 5-8, p < 0.05) by 113% ± 24.5% and by 100% ± 38.2% and in HAP (n = 13-15, p < 0.05) by 625% ± 169% and by 196% ± 23.5%, respectively. Carbachol (1 µM) alone exerted a rapid transient maximum negative inotropic effect in LA (n = 6) and HAP (n = 14) to 46.9% ± 3.63% and 19.4% ± 3.74%, respectively (p < 0.05). These negative inotropic effects were smaller in LA (n = 4-6) and HAP (n = 9-12) pretreated with 100 µM cantharidin and amounted to 58.0% ± 2.27% and 59.2% ± 6.19% or 3 mM sodium fluoride to 63.7% ± 9.84% and 46.3% ± 5.69%, (p < 0.05). We suggest that carbachol, at least in part, exerts a negative inotropic effect in the human atrium by stimulating the enzymatic activity of PP1 and/or PP2A.
卡巴胆碱是一种毒蕈碱受体激动剂，可对人的心房产生负性肌力作用。卡巴胆碱能激活蛋白磷酸酶（PP1或PP2A）。我们推测，PP1和PP2A的抑制剂斑蝥素或氟化钠可能会减弱卡巴胆碱的负性肌力作用。在心脏搭桥手术期间获取人的心房组织（HAP）的心肌小梁。将这些小梁安装在器官浴槽中并进行电刺激（1Hz）。在等长条件下测量收缩力。为作比较，我们研究了从小鼠分离得到的电刺激左心房组织（LA）。斑蝥素（100µM）和氟化钠（3mM）使LA（n = 5 - 8，p < 0.05）的收缩力分别增加了113%±24.5%和100%±38.2%，使HAP（n = 13 - 15，p < 0.05）的收缩力分别增加了625%±169%和196%±23.5%。单独使用卡巴胆碱（1µM）对LA（n = 6）和HAP（n = 14）迅速产生短暂的最大负性肌力作用，分别降至46.9%±3.63%和19.4%±3.74%（p < 0.05）。在用100µM斑蝥素预处理的LA（n = 4 - 6）和HAP（n = 9 - 12）中，这些负性肌力作用较小，分别为58.0%±2.27%和59.
