Mechanisms underlying the impaired EDHF-type relaxation response in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats
Mechanisms underlying the impaired EDHF-type relaxation response in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats
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DOI：
10.1016/j.ejphar.2006.04.006
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发表时间：
2006-05-24
影响因子：
5
通讯作者：
Kamata, Katsuo
中科院分区：
文献类型：
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作者：
Matsumoto, Takayuki;Kobayashi, Tsuneo;Kamata, Katsuo
我们以前报道，在肠系膜动脉链脲佐菌素诱导的糖尿病大鼠，内皮衍生的超极化因子（EDHF）型松弛受损，可能是由于减少行动的cAMP。在这里，我们观察到2型糖尿病模型，大冢Long-Evans德岛脂肪（OLETF）大鼠[与年龄匹配的对照组Long-Evans德岛大冢（LETO）大鼠]肠系膜动脉乙酰胆碱诱导的EDHF型舒张功能受损，我们研究了这种受损的机制。在LETO组中，这种EDHF型舒张被18 α-大黄酸（一种间隙连接抑制剂）和蛋白激酶A（PKA）抑制剂减弱。在这两个组（OLETF和LETO），它增强了3-异丁基-1-甲基黄嘌呤，cAMP-磷酸二酯酶（PDE）抑制剂，但这些增强后，它仍然是弱于OLETF大鼠比LETO大鼠。在OLETF大鼠中，西洛酰胺（一种选择性PDE 3抑制剂）和8-溴-cAMP（一种细胞渗透性cAMP类似物）诱导的舒张作用降低，PKA活性也降低。钙激活钾通道（K-Ca）的两种激活剂[1-乙基-2-苯并咪唑啉酮（1-EBIO），中电导KCa通道（IKCa）激活剂和利鲁唑，小电导KCa通道（SKCa）激活剂]诱导的舒张作用也在OLETF大鼠中受损。我们的结论是，在OLETF大鼠EDHF型松弛的损害可能是由于不仅减少cAMP/PKA信号，但也减少内皮细胞K-Ca通道的活动。(c)2006 Elsevier B. V.保留所有权利。
We previously reported that in mesenteric arteries from streptozotocin-induced diabetic rats, the endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP. Here, we observed an impairment of acetylcholine-induced EDHF-type relaxation in mesenteric arteries from a type 2 diabetic model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats], and we investigated the mechanism underlying this impairment. In the LETO group, this EDHF-type relaxation was attenuated by 18 alpha-glycyrrhetinic acid (a gap-junction inhibitor) and by a protein kinase A (PKA) inhibitor. In both groups (OLETF and LETO), it was enhanced by 3-isobutyl-1-methylxanthine, a cAMP-phosphodiesterase (PDE) inhibitor, but following these enhancements it was still weaker in OLETF rats than in LETO rats. The relaxations induced by cilostamide (a selective PDE3 inhibitor) and 8-bromo-cAMP (a cell-permeant cAMP analog) were reduced in OLETF rats, as was PKA activity. The relaxations induced by two activators of Ca2+- activated K+ channels (K-Ca) [1-ethyl-2-benzimidazolinone (1-EBIO), intermediate-conductance KCa channel (IKCa) activator, and riluzole, small-conductance KCa channel (SKCa) activator] were also impaired in OLETF rats. We conclude that the impairment of EDHF-type relaxation seen in OLETF rats may be attributable not only to a reduction in cAMP/PKA signaling, but also to reduced endothelial K-Ca channel activities. (c) 2006 Elsevier B.V. All rights reserved.