Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, 06097 Halle (Saale), Germany.
Cardiac Surgery, Medical Faculty, Martin Luther University Halle-Wittenberg, 06097 Halle (Saale), Germany.
Eur J Pharmacol. 2018 Jul 5;830:47-58. doi: 10.1016/j.ejphar.2018.04.013. Epub 2018 Apr 17.
We previously reported that uridine 5'-triphosphate (UTP), a pyrimidine nucleoside triphosphate produced a concentration- and time-dependent increase in the contraction force in isolated right atrial preparations from patients undergoing cardiac bypass surgery due to angina pectoris. The stimulation of the force of contraction was sustained rather than transient. In the present study, we tried to elucidate the underlying receptor and signal transduction for this effect of UTP. Therefore, we measured the effect of UTP on force of contraction, phosphorylation of p38 and ERK1/2, in human atrial preparations, atrial preparations from genetically modified mice, cardiomyocytes from adult mice and cardiomyocytes from neonatal rats. UTP exerted a positive inotropic effect in isolated electrically driven left atrial preparations from wild-type (WT) mice and P2Y-, P2Y- and P2Y-receptor knockout mice. Therefore, we concluded that these P2Y receptors did not mediate the inotropic effects of UTP in atrial preparations from mice. However, UTP (like ATP) increased the phosphorylation states of p38 and ERK1/2 in neonatal rat cardiomyocytes, adult mouse cardiomyocytes and human atrial tissue in vitro. U0126, a MEK 1/2- signal cascade inhibitor, attenuated this phosphorylation and the positive inotropic effects of UTP in murine and human atrial preparations. We suggest that presently unknown receptors mediate the positive inotropic effect of UTP in murine and human atria. We hypothesize that UTP stimulates inotropy via p38 or ERK1/2 phosphorylation. We speculate that UTP may be a valuable target in the development of new drugs aimed at treating human systolic heart failure.
我们之前报道过，尿嘧啶 5'-三磷酸（UTP）是一种嘧啶核苷三磷酸，可导致心绞痛患者心脏搭桥手术中的右心房分离标本的收缩力呈浓度和时间依赖性增加。这种收缩力的刺激是持续的，而不是短暂的。在本研究中，我们试图阐明 UTP 产生这种作用的潜在受体和信号转导机制。因此，我们测量了 UTP 对力的收缩，p38 和 ERK1/2 的磷酸化作用，在人心房标本，基因修饰的小鼠心房标本，成年小鼠心肌细胞和新生大鼠心肌细胞中的作用。UTP 对野生型（WT）小鼠和 P2Y-、P2Y-和 P2Y-受体基因敲除小鼠的电驱动左心房分离标本有正性变力作用。因此，我们得出结论，这些 P2Y 受体并不介导 UTP 在小鼠心房标本中的变力作用。然而，UTP（像 ATP 一样）增加了新生大鼠心肌细胞、成年小鼠心肌细胞和人心房组织中 p38 和 ERK1/2 的磷酸化状态。MEK 1/2-信号级联抑制剂 U0126 减弱了这种磷酸化作用和 UTP 在小鼠和人心房标本中的正性变力作用。我们认为，目前未知的受体介导 UTP 在小鼠和人心房中的正性变力作用。我们假设 UTP 通过 p38 或 ERK1/2 磷酸化刺激变力作用。我们推测 UTP 可能是开发用于治疗人类收缩性心力衰竭的新药的有价值的靶点。
