Matsumoto Takayuki, Kobayashi Tsuneo, Wakabayashi Kentaro, Kamata Katsuo
Dept. of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi Univ., Shinagawa-ku, Tokyo, Japan.
Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H1933-40. doi: 10.1152/ajpheart.00303.2005. Epub 2005 May 20.
We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064-H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-alpha) protein was significantly decreased, but the regulatory subunit RII-beta was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
我们之前报道过，在链脲佐菌素（STZ）诱导的糖尿病大鼠的肠系膜动脉中，1）内皮源性超极化因子（EDHF）介导的舒张功能受损，这可能是由于磷酸二酯酶3（PDE3）活性增加导致cAMP作用减弱所致（Matsumoto T、Kobayashi T和Kamata K.《美国生理学杂志：心脏和循环生理学》285: H283 - H291, 2003）；2）蛋白激酶A（PKA）活性降低（Matsumoto T、Wakabayashi K、Kobayashi T和Kamata K.《美国生理学杂志：心脏和循环生理学》287: H1064 - H1071, 2004）。在此，我们研究了PDE3抑制剂西洛他唑的长期治疗是否能改善从STZ大鼠分离出肠系膜动脉的EDHF介导的舒张功能。我们发现，在这些动脉中，1）西洛他唑治疗（2周）改善了乙酰胆碱（ACh）、A - 23187和环匹阿尼酸诱导的EDHF介导的舒张；2）在西洛他唑治疗的STZ大鼠的动脉中，ACh诱导的cAMP积累短暂且持续；3）PKA抑制剂使西洛他唑治疗组的EDHF介导的舒张显著降低，但未治疗组则未出现此现象；4）西洛他唑治疗改善了cAMP类似物诱导的舒张以及PKA活性水平；5）PKA催化亚基（Cat - alpha）蛋白显著降低，但调节亚基RII - beta增加（西洛他唑治疗可显著减弱后者的作用）。这些结果有力地表明，西洛他唑通过增加cAMP和PKA信号传导来改善STZ大鼠的EDHF介导的舒张。
