A novel phospholipase C- and cAMP-independent positive inotropic mechanism via a P2 purinoceptor.
A novel phospholipase C- and cAMP-independent positive inotropic mechanism via a P2 purinoceptor.
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一种通过 P2 嘌呤受体实现的新型磷脂酶 C 和 cAMP 独立正性肌力机制。
DOI：
10.1152/ajpheart.1997.273.5.h2380
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Liang,BT
中科院分区：
文献类型：
--
作者：
Podrasky,E;Xu,D;Liang,BT
尽管 ATP 通过 P2 嘌呤受体发挥作用，可以刺激心室肌细胞产生明显的正性肌力作用，但这种刺激心脏作用的受体效应机制尚不清楚。本研究的目的是开发培养的鸡胚心室肌细胞作为心脏 P2 嘌呤受体的新模型，并确定其正性肌力作用的机制。 ATP 导致肌细胞收缩力增加 89 ± 8.9%（n= 14 个细胞），功效和效力顺序为 ATP > ADP > AMP ≫ 腺苷。 2-甲硫基-ATP (2-MeS-ATP) 但不是 α,β-亚甲基-ATP 能够刺激心肌细胞收缩力，最大增加 54 ± 2.6%（n = 11 个细胞）。尽管 UTP 有效刺激磷酸肌醇水解，但它仅具有适度的正性肌力作用（最大增加 27 ± 7%；n= 8 个细胞）。与之前的建议相反，2-MeS-ATP 刺激的正性肌力反应不需要磷脂酶 C (PLC) 的作用，例如磷酸肌醇的作用； UTP 对收缩性的影响似乎是通过 2-MeS-ATP 敏感的 P2 受体介导的。 PLC 抑制剂 U-73122 对 2-MeS-ATP 刺激的收缩力增加没有影响，这进一步证明了 PLC 在 2-MeS-ATP 的正性肌力作用中的作用。腺苷 3',5'-环单磷酸独立的 Ca2+ 进入刺激机制似乎是受体与心肌细胞收缩力刺激直接偶联的基础。这种新的 PLC 和腺苷 3',5'-环单磷酸独立的正性肌力机制代表了开发新型正性肌力疗法的目标。
Although ATP, acting through a P2 purinoceptor, can stimulate a pronounced positive inotropic effect in cardiac ventricular myocytes, the receptor-effector mechanism that underlies this stimulatory cardiac action is not well understood. The objectives of the present study were to develop the cultured chick embryo ventricular myocytes as a novel model for the cardiac P2 purinoceptor and to determine the mechanism underlying its positive inotropic effect. ATP caused an 89 ± 8.9% (n= 14 cells) increase in the myocyte contractility, with an efficacy and potency order of ATP > ADP > AMP ≫ adenosine. 2-Methylthio-ATP (2-MeS-ATP) but not α,β-methylene-ATP was able to stimulate myocyte contractility, with a maximal increase of 54 ± 2.6% (n= 11 cells). Although UTP potently stimulates phosphoinositide hydrolysis, it had an only modest positive inotropic effect (27 ± 7% maximal increase;n= 8 cells). In contrast to previous suggestions, the 2-MeS-ATP-stimulated positive inotropic response does not require the action of phospholipase C (PLC), such as that of the inositol phosphates; the UTP effect on contractility appears to be mediated via the 2-MeS-ATP-sensitive P2 receptor. The PLC inhibitor U-73122 had no effect on the 2-MeS-ATP-stimulated increase in contractility, providing further evidence against a role for PLC in the inotropic effect of 2-MeS-ATP. An adenosine 3′,5′-cyclic monophosphate-independent Ca2+entry-stimulating mechanism appears to underlie a direct coupling of the receptor to stimulation of the myocyte contractility. This new PLC- and adenosine 3′,5′-cyclic monophosphate-independent positive inotropic mechanism represents a target for developing novel positive inotropic therapeutics.