CONTROL OF CARDIAC-MUSCLE CELL-FUNCTION BY AN ENDOGENOUS NITRIC-OXIDE SIGNALING SYSTEM
CONTROL OF CARDIAC-MUSCLE CELL-FUNCTION BY AN ENDOGENOUS NITRIC-OXIDE SIGNALING SYSTEM
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DOI：
10.1073/pnas.90.1.347
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发表时间：
1993-01-01
影响因子：
11.1
通讯作者：
MICHEL, T
中科院分区：
文献类型：
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作者：
BALLIGAND, JL;KELLY, RA;MICHEL, T
由L-精氨酸合成的一氧化氮（NO）是一种普遍存在的细胞内化学信使，参与多种哺乳动物细胞（包括血管内皮细胞和神经组织）的信号转导。NO信号通路在直接调节心脏功能中的作用尚不清楚。在这份报告中，一氧化氮合酶（NOS）的抑制剂的影响进行了检查，在隔离的新生儿和成年大鼠心室肌细胞暴露于毒蕈碱或肾上腺素能激动剂。卡巴胆碱（10 μ M）对培养的新生大鼠心肌细胞的自发搏动率有91%的抑制作用。N（ω）-单甲基-L-精氨酸，一种L-精氨酸类似物，抑制NOS，和亚甲蓝，一种NO的抑制剂，阻断卡巴胆碱的负性变时作用，但对这些细胞的基础搏动率没有影响。N（ω）-单甲基-L-精氨酸对卡巴胆碱负性变时作用的抑制作用可被添加N-ω-L-精氨酸逆转。卡巴胆碱的负性变时作用也被cGMP类似物模仿，cGMP是一种涉及介导NO在其他细胞类型中作用的第二信使。通过使用报告细胞生物测定法，可以直接在卡巴胆碱刺激的新生心肌细胞中检测到NO的产生。在成人心肌细胞收缩力的研究中也记录了NO信号系统对肾上腺素能反应的调节。NOS抑制剂N（ω）-硝基-L-精氨酸显着增加β-肾上腺素能激动剂异丙肾上腺素对电刺激成年大鼠心室肌细胞的变力作用，而这种抑制剂对基础收缩力没有影响。通过报告细胞生物测定法测定，在这些细胞中，N（ω）-单甲基-L-精氨酸对NO产生的抑制作用在过量的L-精氨酸下也是可逆的。因此，分离的新生儿和成人心室肌细胞对毒蕈碱胆碱能和β-肾上腺素能刺激的生理反应至少部分是由内源性NOS的产物介导的。
Nitric oxide (NO) synthesized from L-arginine is a ubiquitous intracellular chemical messenger and is involved in signal transduction in diverse mammalian cells, including vascular endothelium and neuronal tissues. The role of the NO-signaling pathway in the direct modulation of cardiac function is less well characterized. In this report, the effects of inhibitors of NO synthase (NOS) were examined in isolated neonatal and adult rat ventricular myocytes exposed to either muscarinic or adrenergic agonists. Carbachol (10 muM) caused a 91% inhibition of the spontaneous beating rate of cultured neonatal rat cardiac myocytes. N(omega)-monomethyl-L-arginine, an L-arginine analog that inhibits NOS, and methylene blue, an inhibitor of NO, blocked the negative chronotropic effect of carbachol but had no effect on the basal beating rate of these cells. The inhibition by N(omega)-monomethyl-L-arginine of the negative chronotropic effect of carbachol was reversed by adding exceSS L-arginine. The negative chronotropic effect of carbachol was also mimicked by analogs of cGMP, a second messenger implicated in mediating the action of NO in other cell types. Production of NO could be detected directly in carbachol-stimulated neonatal myocytes by using a reporter cell bioassay. The regulation of adrenergic responsiveness by the NO signaling system was also documented in studies of adult cardiac myocyte contractility. The NOS inhibitor N(omega)-nitro-L-arginine significantly increased the inotropic effect of the beta-adrenergic agonist isoproterenol on electrically stimulated adult rat ventricular myocytes, whereas this inhibitor had no effect on basal contractility. Inhibition of NO production by N(omega)-monomethyl-L-arginine in these cells, as measured by reporter cell bioassay, was also reversible with excess L-arginine. Thus, the physiologic response of isolated neonatal and adult ventricular myocytes to both muscarinic cholinergic and beta-adrenergic stimulation is mediated, at least in part, by products of an endogenous NOS.