Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany.
Department of Cardiac Surgery, Mid-German Heart Center, University Hospital Halle, D-06097 Halle, Germany.
Toxicol Lett. 2023 Jul 1;383:112-120. doi: 10.1016/j.toxlet.2023.06.012. Epub 2023 Jun 30.
We measured the cardiac contractile effects of the sympathomimetic amphetamine-like drug methamphetamine alone and in the presence of cocaine or propranolol in human atrial preparations. For a more comprehensive analysis, we also examined the effects of methamphetamine in preparations from the left and right atria of mice and, for comparison, analyzed the cardiac effects of amphetamine itself. In human atrial preparations, methamphetamine and amphetamine increased the contractile force, the relaxation rate, and the rate of tension development, and shortened the time to maximum tension and the time to relaxation. Likewise, in mice preparations, methamphetamine and amphetamine increased the contractile force in the left atrium and increased the beating rate in the right atrium. The effect in human atrial preparations started at 1 µM, therefore methamphetamine was less effective and potent than isoproterenol in increasing contractile force. These positive inotropic effects of methamphetamine were greatly attenuated by 10 µM cocaine and abolished by 10 µM propranolol. The inotropic effects of methamphetamine in human atrial preparations were associated with, and are believed to be mediated at least in part by, an increase in the phosphorylation state of the inhibitory subunit of troponin. In conclusion, the sympathomimetic central stimulant drug methamphetamine (as well as amphetamine) increased contractile force and protein phosphorylation, presumably through a release of noradrenaline in isolated human atrial preparations. Thus, methamphetamine acts as an indirect sympathomimetic in the human atrium.
我们测量了拟交感胺苯丙胺类药物甲基苯丙胺单独作用以及与可卡因或普萘洛尔共同作用对人心房组织的收缩效应。为了进行更全面的分析，我们还研究了甲基苯丙胺对来自小鼠左右心房组织的作用，并比较分析了安非他命本身对心脏的影响。在人心房组织中，甲基苯丙胺和安非他命增加了收缩力、松弛率和张力发展速度，并缩短了达到最大张力和松弛的时间。同样，在小鼠的心房组织中，甲基苯丙胺和安非他命增加了左心房的收缩力，并增加了右心房的跳动率。在人心房组织中的作用起始于 1µM，因此，与异丙肾上腺素相比，甲基苯丙胺在增加收缩力方面的效果较弱且效力较低。10µM 可卡因极大地减弱了甲基苯丙胺的正性变力作用，而 10µM 普萘洛尔则完全消除了其作用。甲基苯丙胺在人心房组织中的变力作用与肌钙蛋白抑制亚单位的磷酸化状态增加有关，并且据信至少部分通过这种增加来介导。总之，拟交感神经中枢兴奋剂甲基苯丙胺（以及安非他命）增加了收缩力和蛋白磷酸化，可能是通过在人心房组织中释放去甲肾上腺素。因此，甲基苯丙胺在人心房组织中作为一种间接拟交感神经兴奋剂起作用。
