Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes
Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes
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DOI：
10.1161/hh1701.095716
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发表时间：
2001-08-31
影响因子：
20.1
通讯作者：
Sollott, SJ
中科院分区：
文献类型：
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作者：
Petroff, MGV;Egan, JM;Sollott, SJ
肠道激素胰高血糖素样肽-1 (GLP-1) 响应肠腔中的营养物质而以纳摩尔量分泌，在靶内分泌组织中发挥 cAMP/蛋白激酶 A 介导的促胰岛素作用，但其在心脏细胞中的作用尚不清楚。 GLP-1 (10 nmol/L) 增加大鼠心肌细胞内的 cAMP（从 5.7+/-0.5 至 13.1 +/- 0.12 pmol/mg 蛋白质）。比较了 GLP-1 和异丙肾上腺素 (ISO. 10 nmol/L) 的 cAMP 加倍浓度对 indo-1 和 seminaphthorhodaflu (SNARF)-1 负载的肌细胞的收缩幅度、细胞内 Ca2+ 瞬变 (CaT) 和 pH(i) 的影响。 ISO 引起收缩幅度 (160+/-34%) 和 CaT (70+/-5%) 特征性增加（高于基线），而 GLP-1 则引起收缩幅度显着降低 (-27+/-5%)，20 分钟后 CaT 没有变化。百日咳毒素治疗或暴露于 cGMP 刺激的磷酸二酯酶 (PDE2) 抑制剂赤-9-(2-羟基-3-壬基)腺嘌呤或非选择性 PDE 抑制剂 3-异丁基-1-甲基黄嘌呤或磷酸酶抑制剂冈田酸或花萼蛋白 A 均未揭示 GLP-1 的 ISO 模拟反应。然而，在负载 SNARF-1 的肌细胞中，ISO 和 GLP-1 均引起细胞内酸中毒（Delta pH(i) 分别为 -0.09+/-0.02 和 -0.08+/-0.03）。特异性 GLP-1 拮抗剂 exendin 9-39 和 cAMP 抑制类似物 Rp-8CPT-cAMPS 抑制 GLP-1 诱导的细胞内酸中毒和负收缩效应。我们得出的结论是，与β-肾上腺素能信号传导相反，GLP-1增加cAMP但不能增强收缩，这表明存在功能不同的腺苷酸环化酶/cAMP/蛋白激酶A区室，这可能是由不受百日咳毒素敏感的G蛋白或增强的局部PDE或磷酸酶激活控制的独特受体信号传导微结构域决定的。此外，GLP-1 还可引起 cAMP 依赖性适度的负性肌力作用，这种作用是由细胞内酸化导致的肌丝 Ca2+ 反应性降低而产生的。
The gut hormone, glucagon-like peptide-1 (GLP-1), which is secreted in nanomolar amounts in response to nutrients in the intestinal lumen, exerts cAMP/protein kinase A-mediated insulinotropic actions in target endocrine tissues, but its actions in heart cells are unknown. GLP-1 (10 nmol/L) increased intracellular cAMP (from 5.7+/-0.5 to 13.1 +/- 0.12 pmol/mg protein) in rat cardiac myocytes. The effects of cAMP-doubling concentrations of both GLP-1 and isoproterenol (ISO. 10 nmol/L) on contraction amplitude, intracellular Ca2+ transient (CaT), and pH(i) in indo-1 and seminaphthorhodafluor (SNARF)-1 loaded myocytes were compared. Whereas ISO caused a characteristic increase (above baseline) in contraction amplitude (160+/-34%) and CaT (70+/-5%), GLP-1 induced a significant decrease in contraction amplitude (-27+/-5%) with no change in the CaT after 20 minutes. Neither pertussis toxin treatment nor exposure to the cGMP-stimulated phosphodiesterase (PDE2) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine or the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine nor the phosphatase inhibitors okadaic acid or calyculin A unmasked an ISO-mimicking response of GLP-1. In SNARF-1-loaded myocytes, however, both ISO and GLP-1 caused an intracellular acidosis (Delta pH(i) -0.09+/-0.02 and -0.08+/-0.03, respectively). The specific GLP-1 antagonist exendin 9-39 and the cAMP inhibitory analog Rp-8CPT-cAMPS inhibited both the GLP-1-induced intracellular acidosis and the negative contractile effect. We conclude that in contrast to beta -adrenergic signaling, GLP-1 increases cAMP but fails to augment contraction, suggesting the existence of functionally distinct adenylyl cyclase/cAMP/protein kinase A compartments, possibly determined by unique receptor signaling microdomains that are not controlled by pertussis toxin-sensitive G proteins or by enhanced local PDE or phosphatase activation. Furthermore, GLP-1 elicits a cAMP-dependent modest negative inotropic effect produced by a decrease in myofilament-Ca2+ responsiveness probably resulting from intracellular acidification.