Mechanisms Associated to Nitroxyl (HNO)-Induced Relaxation in the Intestinal Smooth Muscle
Mechanisms Associated to Nitroxyl (HNO)-Induced Relaxation in the Intestinal Smooth Muscle
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DOI：
10.3389/fphys.2020.00438
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发表时间：
2020-06-03
影响因子：
4
通讯作者：
Pouokam, Ervice
中科院分区：
文献类型：
--
作者：
Gastreich-Seelig, Mirko;Jimenez, Marcel;Pouokam, Ervice
硝酰基（HNO）供体在胃肠道中的药理学特性尚不清楚。我们研究了这种分子在调节胃肠收缩中的特性，重点是它与其他气体信号分子如NO和H2S的可能相互作用。用Angeli盐作为HNO供体，对大鼠肠道样品进行器官浴、Ca（2+）成像和微电极记录。Angeli盐引起回肠和近端结肠的纵向或环形肌条的浓度依赖性松弛。Rho激酶抑制剂Y-27632（10 μ M）、还原剂DTT或可溶性鸟苷酸环化酶（sGC）ODQ抑制剂（10 μ M）单独或与内源性H2S β-氰基-L-丙氨酸（5 mM）和氨基-氧乙酸（5 mM）合成抑制剂组合强烈抑制这种松弛。防止内源性合成NO的NO合成酶抑制剂L-NAME（200 μ M）没有影响松弛诱导HNO。HNO引起结肠肌细胞内Ca（2+）浓度升高。它还引起肌细胞膜超极化，达到-10.6 +/- 1.1 mV。ODQ（10 μ M）和Apamin（1 μ M），一种小电导Ca ~（2+）激活的K（+）通道（SKca）的选择性抑制剂，强烈拮抗这种作用。我们的结论是，HNO通过与NO类似的sGC/cGMP途径的激活通过超极化肌细胞来松弛胃肠道肌肉组织，不仅抑制RhoK和激活MLCP，如NO和H2S，而且增加细胞溶质Ca（2+）以激活SK（C）（a），从而促进超极化。
The pharmacological properties of nitroxyl (HNO) donors in the gastrointestinal tract are unknown. We investigated the properties of this molecule in the regulation of gastrointestinal contractility focusing on its possible interaction with other gaseous signaling molecules such as NO and H2S. Organ bath, Ca(2+)imaging, and microelectrode recordings were performed on rat intestinal samples, using Angeli's salt as HNO donor. Angeli's salt caused a concentration-dependent relaxation of longitudinal or circular muscle strips of the ileum and the proximal colon. This relaxation was strongly inhibited by the Rho-kinase inhibitor Y-27632 (10 mu M), by the reducing agent DTT or by the inhibitor of soluble guanylate cyclase (sGC) ODQ (10 mu M) alone or in combination with the inhibitors of the endogenous synthesis of H2S beta-cyano-L-alanine (5 mM) and amino-oxyacetate (5 mM). Preventing endogenous synthesis of NO by the NO synthase inhibitor L-NAME (200 mu M) did not affect the relaxation induced by HNO. HNO induced an increase in cytosolic Ca(2+)concentration in colonic myocytes. It also elicited myocyte membrane hyperpolarization that amounted to -10.6 +/- 1.1 mV. ODQ (10 mu M) and Apamin (1 mu M), a selective inhibitor of small conductance Ca2+-activated K(+)channels (SKca), strongly antagonized this effect. We conclude that HNO relaxes the gastrointestinal tract musculature by hyperpolarizing myocytes via activation of the sGC/cGMP pathway similarly to NO, not only inhibiting the RhoK and activating MLCP as do both NO and H2S but also increasing cytosolic Ca(2+)for activation of SK(C)(a)contributing to hyperpolarization.