心肌肥厚时κ阿片受体介导的信号通路受损(英文)

目的:分离正常及慢性缺氧性有心肥厚的心室肌细胞,观察细胞内Ca~(2 )]_i及细胞内pH_i对心肌к-阿片受体激动后的反应。方法:以fura-2和BCECF分别为Ca~(2 )]_i和pH_i的指示剂,用光谱荧光法测定电刺激引起的细胞内Ca~(2 )]_i瞬变及pH_i。结果:к阿片受体选择性激动剂U50,488H可降低电刺激引起的Ca~(2 )]_i瞬变和增加pH_i,该作用是由蛋白激酶C(PKC)所介导。在肥厚的心室肌细胞,U50,488H的上述作用显著减弱。与此相对应,PKC的激动剂PMA引起的Ca~(2 )]_i瞬变降低和pH_i的增加作用在肥厚的心室肌细胞亦消失。用NH_4Cl法观察Na~ -H~ 交换器的功能显示其在肥厚的心室肌细胞无明显改变。结论:心肌肥厚时к-阿片受体介导的信号通路受损,受损部位发生在PKC与效应器之间。

Signaling pathway mediated by K-opioid receptor is impaired in cardiac hypertrophy

AIM: The responses of the intracellular calcium (Ca2 ]i) and the intracellular pH (pHi) to k-opioid receptor stimulation were determined in the single right ventricular myocytes isolated from the hearts of chronically hypoxic rats which exhibited right ventricular hypertrophy (RVH). METHODS: With the spectrofluoro-metric method, the electrically-induced Ca2 ], transient and pHi were measured in myocytes loaded with fura-2 and BCECF 2', 7'-bis-(2-carboxyethyl)-5-( and 6)-carboxyfluorscein], respectively. RESULTS: U50,488H, a selective k-opioid agonist decreased the electrically-induced Ca2 ]i transient and increased the pHi. The effect of U50,488H was mediated by protein kinase C (PKC). In the RVH, the effect of U50,488H on the Ca2 ]i transient and the pHj were significantly attenuated. In parallel, 4-phorbol 12-myristate 13-acetate (PMA), an activator of PKC, also decreased the Ca2 ]i transient and increased the pHi. In the RVH, the effects of PMA were blunted. The recovery of pHi, which was blocked by ethylisopropyl-amiloride (EIPA), following an acid loading induced by washout of 10 mmol/L NH4Cl exposing to the cells for 10 min was the same in the RVH and control myocytes. CONCLUSION: k-Opioid receptor signaling was impaired in the cardiac hypertrophy due to a defect in the coupling of PKC signaling with its effector.