排序方式: 共有44条查询结果,搜索用时 15 毫秒
31.
Giuseppe Caliendo Paolo Grieco Elisa Perissutti Vincenzo Santagada Antonello Santini Stefania Albrizio Caterina Fattorusso Aldo Pinto Raffaella Sorrentino 《European journal of medicinal chemistry》1998,33(12):957-967
With the aim of discovering new molecules with K+-channel activating properties, we have synthesized derivatives of cromakalim (CRK), an important molecule which shows specific affinity towards K+ channels, by replacing the benzopyrane ring of this reference compound with a 1,4-benzoxazine moiety. A different number of substituents showing a good discrimination between hydrophobic and electronic properties have been inserted at the 6-position of the 1,4-benzoxazine ring. We describe here the synthesis and discuss the solid state conformation of these new molecules. When tested on rat aorta ring precontracted with phenylephrine, two compounds (2c and 2d) showed a concentration-dependent relaxation similar to that measured for cromakalim but less potent than this reference drug. 相似文献
32.
Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery 总被引:4,自引:0,他引:4
Pataricza J Krassói I Höhn J Kun A Papp JG 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2003,17(2):115-121
Levosimendan, a new type of inodilator drugs, is known to activate membrane adenosine 3,5-triphosphate-sensitive potassium (KATP) channels in some vascular smooth muscles and causes vasorelaxation. The involvement of potassium channels in the mechanism of the coronary artery relaxing effect of the drug has not been established. In the present study performed in the porcine epicardial coronary artery, the effect of levosimendan (0.009–3.2 M) was compared to cromakalim (0.0125–5 M), the known activator of ATP-sensitive potassium (KATP) channels, in the presence of glibenclamide (GLI), an inhibitor of KATP channels and tetraethylammonium (TEA), the non-selective inhibitor of potassium channels. The interaction of levosimendan with the specific calcium-activated potassium channel (KCa) blocker, iberiotoxin (IBTX), and the voltage-sensitive potassium channel (KV) blocker, 4-aminopyridine (4-AP), was also studied. All the experiments were performed in the isometric tension of endothelium denuded porcine isolated epicardial coronary arteries precontracted with 20 mM potassium chloride. 1 M GLI decreased the maximum of cromakalim-induced relaxation by 60% but did not affect the action of levosimendan. In contrast, 2 mM TEA decreased only the coronary artery relaxing effect of levosimendan. 100 nM IBTX suppressed the maximum effect of levosimendan by only 15% while 0.5 mM 4-AP significantly shifted the concentration-response curve of the inodilator to the right. 5 mM 4-AP caused a maximum of 33% decrease of levosimendan-induced relaxation. These results indicate that, in porcine isolated epicardial coronary artery, the vasorelaxing mechanism of levosimendan involves the activation of voltage-sensitive and, at large concentrations, calcium-activated potassium channels. 相似文献
33.
BACKGROUND:Studies have reported that potassium channel openers exhibit a protective effect on cerebral ischemia-reperfusion injury and inhibit glutamate excitotoxicity in rats.However,the effects of the glutamate receptor 1α and glutamate transporter 1 remain poorly understood.OBJECTIVE:To investigate the prophylactic use of the adenosine triphosphate-sensitive potassium channel opener cromakalim on neurological function and cerebral infarct size,as well as glutamate receptor 1α and glutamate transporter 1 expression,in rats with cerebral ischemia-reperfusion injury,and to explore action mechanisms underlying reduced glutamate excitotoxicity and neuroprotection in rats.DESIGN,TIME AND SETTING:Randomized,controlled,animal experiment was performed at the Brain Institute,Qingdao University Medical College,Between July 2008 and April 2009.MATERIALS:Cromakalim was purchased from Sigma,USA; rabbit anti-glutamate receptor 1α polyclonal antibody was offered by Wuhan Boster,China; rabbit anti-glutamate transporter 1 polyclonal antibody was offered by Santa Cruz Biotechnology,USA.METHODS:Sixty male,Wistar rats,aged 6 months,were randomly assigned to three groups (n =20):sham-surgery,model,and cromakalim.Intraluminal thread methods were used to establish middle cerebral artery occlusion in rats from the model and cromakalim groups.Rats from the sham-surgery group were subjected to exposed common carotid artery,external carotid artery,and internal carotid artery,without occlusion.Cromakalim (10 mg/kg) was administered 30 minutes prior to middle cerebral artery occlusion,but there was no intervention in the model and sham-surgery groups.MAIN OUTCOME MEASURES:At 24 hours post-surgery,neurological behavioral functions were evaluated using Bederson's test,cerebral infarction volume was determined following tetrazolium chloride staining,and glutamate receptor 1a and glutamate transporter 1 expressions were detected using immunohistochemistry.RESULTS:Following cerebral ischemia-reperfusion injury,neurological behavioral malfunctions were obvious in all mice.Focal cerebral infarction was detected in ischemic hemispheres,glutamate receptor 1α expression increased,and glutamate transporter 1 expression decreased in the ischemic hemisphere (P< 0.05).Compared with the model group,neurological behavioral functions significantly improved,cerebral infarction volume was significantly reduced (P< 0.05),glutamate receptor 1α expression was significantly decreased,and glutamate transporter 1 expression was increased in the cromakalim group (P < 0.05).CONCLUSION:Improved neurological function and reduced cerebral infarction volume in rats through the preventive use of cromakalim could be related to decreased glutamate receptor 1α expression and enhanced glutamate transporter 1 expression. 相似文献
34.
克罗卡林对不同年龄大鼠血管平滑肌张力作用的影响 总被引:3,自引:1,他引:3
目的研究钾通道开放剂克罗卡林(cromakalim)对不同年龄大鼠血管平滑肌张力作用的影响。方法大鼠离体血管平滑肌张力记录法。结果cromakalim可抑制由苯肾上腺素(Phe)介导弓;起的血管收缩,其作用在老年大鼠明显减弱;血管内皮的去除或分别应用NO合酶抑制剂L.NAME、环氧酶抑制剂亚甲蓝,均可明显降低cromakalim的舒血管反应,但内皮去除或NO作用被抑制却消除了cro-makalim作用与年龄变化的关系。此外研究还表明:内源性和外源性NO供体Ach及SNP的舒血管反应在老年大鼠明显弱于幼年大鼠。结论NO释放量的减少或血管对NO反应性的降低可能是引起cromakalim舒血管作用在老年大鼠明显减弱的重要原因。 相似文献
35.
目的观察蛋白激酶A(PKA)及蛋白激酶C(PKC)抑制剂和蛋白脱磷酸化物质对大鼠心室肌细胞ATP敏感性钾电流 (IKATP)的影响 ,探讨克罗卡林 (cromakalim)开放ATP敏感性钾通道的作用机制。方法采用全细胞膜片钳技术记录心室肌细胞IKATP。结果在37℃时克罗卡林 (1μmol·L-1)可阻断ATP的抑制作用 ,诱导出IKATP。PKA抑制剂PKI(6~22)amide (1μmol·L -1),可模拟克罗卡林的作用 ,激活IKATP;而PKC抑制剂calphosticC无此作用。同时还观察到蛋白脱磷酸化物质butanedioemonoxime(BDM,5mmol·L -1)也可诱发出IKATP。结论克罗卡林开放IKATP 机制与抑制PKA的活性有关 ,而与PKC无关。 相似文献
36.
Summary— The effects of nicorandil on systemic blood pressure (SBP) and heart rate (HR) responses to adenosine were compared with those to N6 -cyclopentyladenosine (CPA), a selective adenosine A, receptor agonist, and 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), a selective adenosine A2 receptor agonist, in anesthetized rats. When injected intravenously (iv), single bolus doses of CPCA (0.01–1.0 μg/kg), like adenosine (30 μg/kg), elicited dose-dependent decreases in SBP scarcely affecting HR, while CPA (0.03–1.0 μg/kg) produced only reduction of HR without influencing SBP. The enhancement of the vasodepressor response to CPCA, like adenosine, was induced by the iv infusion of either nicorandil (10 μg/kg per min) or cromakalim (0.1 μg/kg per min), but the response to CPA in HR remained unmodified during the infusion of nicorandil as well as cromakalim. After iv treatment with glibenclamide (20 mg/kg), an adenosine triphosphate (ATP)-sensitive K+ channel blocker, or 3,7-dimethyl-1-propargylxanthine (DMPX) (1 mg/kg), a selective antagonist of adenosine A2 receptor, not only CPCA action but also the enhancement of CPCA action by nicorandil and cromakalim were significantly attenuated. Similar results were obtained in the case of single bolus iv adenosine. The present result indicates that the augmentation of the adenosine action by nicorandil appears to be mediated by activation of ATP-sensitive K+ channels, closely linked with stimulation on A2 receptors by adenosine. 相似文献
37.
38.
KRN2391和克罗卡林对大鼠离体心脏的保护作用 总被引:2,自引:0,他引:2
目的:比较两种不同的 A T P敏感性钾通道开放剂 K R N2391( K R N)和克罗卡林( C R)对大鼠离体心脏心功能的影响及缺血后的心脏保护作用。方法:将离体心脏进行完全缺血 25 m in,观察再灌注30 m in 时心功能的变化。结果:1~20 μm ol/ L K R N 及1~20 μm ol/ L C R均能显著增加冠脉灌流量。20 μm ol/ L K R N 及 10 μm ol/ L C R 可明显降低心脏收缩功能,1 μm ol/ L K R N 和1 μm ol/ L C R较对照组均有改善缺血后心功能的作用,此作用可完全被格列本脲所阻断。结论:两药均有明显冠脉扩张作用,大剂量应用可降低心脏收缩功能,用不影响心功能的剂量两者均有对缺血后心脏的保护作用,此作用与 A T P敏感性钾通道开放有关。 相似文献
39.
An abnormal ratio between Na+ and K+ conductances seems to be the cause for the depolarization and paralysis of skeletal muscle in primary hypokalemic periodic paralysis. Recently we have shown that the "K+ channel opener" cromakalim hyperpolarizes mammalian skeletal muscle fibers. Now we have studied the effects of this drug on the twitch force of muscle biopsies from normal and diseased human skeletal muscle. Cromakalim had little effect on the twitch force of normal muscle whereas it strongly improved the contraction force of fibers from patients suffering from hypokalemic periodic paralysis. Recordings of intracellular K+ and Cl- activities in human muscle and isolated rat soleus muscle support the view that cromakalim enhances the membrane K+ conductance (gK+). These data indicate that "K+ channel openers" may have a beneficial effect in primary hypokalemic periodic paralysis. 相似文献
40.
Fumiya Yoneyama Keisuke Satoh Professor Norio Taira 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》1990,4(4):1119-1126
Summary Nicorandil has a hybrid property between nitrates and potassium (K)-channel openers. In order to clarify which mechanism of action is responsible for its effect in increasing coronary blood flow, we investigated how this effect was antagonized by glibenclamide, which was recently found to behave as a pharmacologic antagonist of K-channel openers. Cromakalim, one of the most specific K-channel openers currently available, and nitroglycerin were used as reference drugs. In isolated, blood-perfused papillary muscle preparations of dogs, intraarterial injections of nicorandil and cromakalim increased (coronary) blood flow, and at high doses a negative inotropic effect and ventricular fibrillation occurred. Dose-response curves for the increase in coronary blood flow produced by nicorandil or cromakalim were shifted to the right in a parallel manner and to similar extents by glibenclamide given intravenously to support dogs. Schild analysis yielded pA2 values of 6.08 and 6.34 for glibenclamide versus nicorandil and cromakalim, respectively. Nitroglycerin injected intraarterially produced only an increase in coronary blood flow. This effect was not affected by glibenclamide. These results indicate that the effect of nicorandil in increasing coronary blood flow, like that of cromakalim, is predominantly due to its mechanism of action as a K-channel opener. The negative inotropy and ventricular fibrillation seen with high doses of nicroandil and cromakalim were also antagonized by glibenclamide, indicating that these effects are also due to K-channel opening. 相似文献