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首页> 外文期刊>Cellular Physiology and Biochemistry >NO underlies the muscarinic receptor-mediated inhibition of I-f in early embryonic heart cells
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NO underlies the muscarinic receptor-mediated inhibition of I-f in early embryonic heart cells

机译：NO是毒蕈碱受体介导的I-f在早期胚胎心脏细胞中的抑制作用的基础

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Background/Aims: Early embryonic cardiomyocytes beat spontaneously. The hyperpolarization-activated cyclic-nucleotide-modulated current (I-f) appears to be involved in its modulation as it is highly expressed at this stage. The spontaneous beating of early embryonic heart cells is slowed by acetylcholine (ACh), and our earlier studies identified a key role for nitric oxide ( NO) in the regulation of the voltage dependent L-type Ca2+ current (I-Ca,I-L). The aim of the present study was to clarify whether and via which signalling pathway(s) I-f is regulated upon muscarinic receptor activation in early embryonic (E9.5 to E11.5) cardiomyocytes. Methods: The whole-cell patch clamp technique in combination with pharmacology and/or knock out mouse models was used to investigate the regulation of I-f. Results: We found that the ACh analogue carbachol (CCh, 10 mu mol) led in the majority of cells (68%, n=50) to a significant depression of I-f by 16.3 +/- 1.4% (n= 34, p < 0.01, voltage steps from -35 mV to -110 mV). This cholinergic inhibition was mediated by the NO/cGMP signalling pathway as it was largely reversed by superfusion with the non selective nitric oxide synthase ( NOS) inhibitor NG-Methyl-L-arginine acetate salt (L-NMMA, 1 mmol), the inhibitor of the soluble guanylyl cyclase (sGC) 1H-[1, 2, 4] Oxadiazolo[4, 3-a] quinoxalin-1-one (ODQ, 100 mu mol) and a selective inhibitor of the phosphodiesterase (PDE) type 2 Erythro-9-(2-hydroxy-3nonyl) adenine ( EHNA, 30 mu mol). Analysis of the muscarinic signalling in embryonic cardiomyocytes harvested from NOS2 (-/-) and NOS3 (-/-) mice revealed that the NOS3 isoform was entirely responsible for the muscarinic receptor-induced NO production. Conclusions: Muscarinic receptor stimulation depresses I-f by generating NO via the NOS3 and the cGMP/PDE type 2 signalling pathway in early embryonic cardiomyocytes. This suggests that NO is a key signalling molecule involved in the regulation of chronotropy of early embryonic heart cells. Copyright (c) 2007 S. Karger AG, Basel.
机译：背景/目的：早期胚胎心肌细胞自发搏动。超极化激活的环核苷酸调制电流（I-f）似乎参与了其调制，因为它在此阶段被高度表达。乙酰胆碱（ACh）减慢了早期胚胎心脏细胞的自发搏动，我们的早期研究发现一氧化氮（NO）在调节电压依赖性L型Ca2 +电流（I-Ca，I-L）中起关键作用。本研究的目的是阐明在早期胚胎（E9.5至E11.5）心肌细胞中毒蕈碱受体激活时是否调控I-f信号传导，以及通过该信号传导途径I-f调控。方法：采用全细胞膜片钳技术结合药理学和/或敲除小鼠模型研究I-f的调控。结果：我们发现ACh类似物卡巴胆碱（CCh，10μmol）导致大多数细胞（68％，n = 50）导致If的显着降低16.3 +/- 1.4％（n = 34，p < 0.01，电压范围从-35 mV到-110 mV）。这种胆碱能抑制作用是由NO / cGMP信号传导途径介导的，因为通过与非选择性一氧化氮合酶（NOS）抑制剂NG-甲基-L-精氨酸乙酸盐（L-NMMA，1 mmol）的超融合被很大程度上逆转了。可溶性鸟苷基环化酶（sGC）1H- [1、2、4]乙二唑并[4，3-a]喹喔啉-1-酮（ODQ，100μmol）和磷酸二酯酶（PDE）2型赤藓糖的选择性抑制剂-9-（2-羟基-3壬基）腺嘌呤（EHNA，30μmol）。对从NOS2（-/-）和NOS3（-/-）小鼠收获的胚胎心肌细胞中毒蕈碱信号的分析表明，NOS3亚型完全由毒蕈碱受体诱导的NO产生。结论：毒蕈碱受体刺激通过NOS3和cGMP / PDE 2型信号通路在早期胚胎心肌细胞中产生NO来抑制I-f。这表明NO是参与早期胚胎心脏细胞变时性调节的关键信号分子。版权所有（c）2007 S.Karger AG，巴塞尔。

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