Involvement of reduced sensitivity to Ca2+ in β-adrenergic action on airway smooth muscle
Involvement of reduced sensitivity to Ca2+ in β-adrenergic action on airway smooth muscle
复制标题
DOI：
10.1111/j.1365-2222.2006.02412.x
复制
发表时间：
2006-02-01
影响因子：
6.1
通讯作者：
Kamiya, K
中科院分区：
文献类型：
--
作者：
Oguma, T;Kume, H;Kamiya, K
众所周知，β -肾上腺素能受体激动剂（β -激动剂）通过降低细胞内Ca2+浓度介导气道平滑肌松弛（[Ca2+](i)）。然而，目前对Ca2+敏化降低是否参与β -肾上腺素能松弛知之甚少。本研究旨在确定β -肾上腺素能松弛（β激动剂Ca2+独立松弛）中Ca2+敏化抑制的细胞内机制。在豚鼠气管平滑肌分离的fura-2负载条中同时测量等长张力和[Ca2+](i)。在异丙肾上腺素（ISO）和其他camp相关药物对甲基苯丙胺诱导的收缩的抑制作用中，研究了张力和[Ca2+](i)之间的关系。在张力条件下，ISO对甲胆碱的浓度抑制曲线与ISO在[Ca2+]中的浓度抑制曲线明显分离(i)。在iso诱导的松弛中，张力的降低明显大于[Ca2+](i)。这一现象被其他camp相关制剂模仿：福斯克林和二丁基camp。相反，非选择性Ca2+通道抑制剂SKF-96365的抑制作用与[Ca2+]中的抑制作用相关(i)。在蛋白激酶A （PKA）抑制剂rp - camp的存在下，ISO引起了等效的松弛，[Ca2+]的减少较少(i)。rho激酶抑制剂Y-27632和蛋白激酶c抑制剂双吲哚酰马来酰亚胺对ISO的作用没有影响。ISO不能抑制肌球蛋白磷酸酶抑制剂calyculin A引起的收缩。β -肾上腺素能作用拮抗不仅Ca2+动员，而且Ca2+敏化在甲胺氯诱导的收缩。与cAMP/ pka依赖途径相比，cAMP/ pka独立的G(s)直接作用在β激动剂的Ca2+非依赖性松弛中更有效。此外，肌球蛋白磷酸酶在β激动剂介导的Ca2+反应降低中是一个基本受影响的蛋白质。我们的研究结果可能提供证据，表明这种Ca2+脱敏是一种使用速效β激动剂的缓解药物在急性哮喘管理中的新靶点。
It is well known that beta-adrenoceptor agonists (beta-agonists) cause relaxation in airway smooth muscle mediated by a reduction in the concentration of intracellular Ca2+ ([Ca2+](i)). However, little is currently known regarding whether reduced sensitization to Ca2+ is involved in the beta-adrenergic relaxation.This study was designed to determine the intracellular mechanisms underlying suppression of Ca2+ sensitization in beta-adrenergic relaxation (Ca2+-independent relaxation by beta-agonists).Isometric tension and [Ca2+](i) were simultaneously measured in fura-2-loaded strips isolated from guinea-pig tracheal smooth muscles. The relationships between tension and [Ca2+](i) were examined in the inhibitory action of isoprenaline (ISO) and other cAMP-related agents against methacholine-induced contraction.The concentration-inhibition curve for ISO against methacholine in tension was significantly dissociated from the curve for ISO in [Ca2+](i). In ISO-induced relaxation, a reduction in tension was significantly greater than that in [Ca2+](i.) This phenomenon was mimicked by other cAMP-related agents: forskolin and dibutyryl-cAMP. In contrast, the inhibitory action of SKF-96365, a non-selective inhibitor of Ca2+ channels, was associated with that in [Ca2+](i). In the presence of Rp-cAMPS, an inhibitor of protein kinase A (PKA), ISO caused an equivalent relaxation with less reduction in [Ca2+](i). The effects of ISO were not affected by Y-27632, an inhibitor of Rho-kinase, or by bisindolylmaleimide, an inhibitor of protein kinase C. ISO failed to inhibit contraction elicited by calyculin A, an inhibitor of myosin phosphatase.beta-Adrenergic action antagonizes not only Ca2+ mobilization but also Ca2+ sensitization in methacholine-induced contraction. The cAMP/PKA-independent, G(s)-direct action is more potent in Ca2+-independent relaxation by beta-agonists than the cAMP/PKA-dependent pathway. Moreover, myosin phosphatase is a fundamentally affected protein in the reduced response to Ca2+ mediated by beta-agonist. Our results may provide evidence that this Ca2+ desensitization is a novel target for a reliever medication using rapid-acting beta-agonists in acute asthma management.