K-ATP channel independent effects of pinacidil on ATP production in isolated cardiomyocyte or pancreatic beta-cell mitochondria

Evidence has been presented that mitochondria contain ATP sensitive potassium channels (mK-ATP channels), which may confer tissue protection upon activation. It is, however, not known whether activation of mK-ATP channels has a direct effect on mitochondrial ATP production. This study was performed to define the effect of pinacidil (PIN) on ATP production by oxidative phosphorylation in isolated cardiomyocyte or pancreatic beta-cell mitochondria. Cardiomyocyte mitochondria produced seven times more ATP than beta-cell mitochondria in the presence of pyruvate/malate. PIN inhibited pyruvate/malate-induced mitochondrial ATP production with half maximal effect at 360 microM in both cell types. The inclusion of 5-hydroxydecanoate (5-HD) did not prevent this inhibition. Succinate induced a similar ATP production in cardiomyocyte or beta-cell mitochondria. In beta-cell mitochondria succinate-induced ATP production was inhibited by PIN with half maximal effects at 500 microM PIN. However, in cardiomyocyte mitochondria PIN stimulated succinate-induced ATP production 3-fold with half maximal effect at 100 microM and maximal effect at 200 microM. This PIN-dependent stimulation was mimicked by rotenone. The inclusion of 5-HD could not prevent these PIN effects. In conclusion, PIN may inhibit complex 1 of the respiratory chain without indications of opening mK-ATP channels. In cardiomyocytes with metabolically inhibited succinate dehydrogenase this results in a stimulation of ATP production conferring tissue protection. In beta-cells without a metabolically inhibited succinate dehydrogenase, there is no stimulation by PIN and tissue protection by PIN is not to be expected.     

中医诊疗技术在国际专利分类表中的分布

《国际专利分类表》(International Patent Classification,IPC)是目前国际通用的管理和利用专利文献的工具。中医诊疗技术专利可按照其运用于诊断或治疗过程的不同分为两大类,主要分布于IPC分类的"A部:人类生活必需的"分部:保健;救生;娱乐"下的"A61医学或兽医学;卫生学"医学部类中。尚有部分依从于其技术结合学科,分布于计算、测量等非医学部类中。对中医诊疗技术专利的IPC分类号进行分析研究,可了解其主题分布与技术布局。     

New role of Notch-mediated signaling pathway in myocardial ischemic preconditioning

Ischemic preconditioning (IPC) is the strongest endogenous myocardial protective mechanism, but up to now, its specific mechanisms have not been completely understood. The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. Recent loss-of-function studies have shown that the Notch1 receptor controls the response to injury in the adult heart by limiting myocyte hypertrophy, enhancing myocyte survival, promoting precursor proliferation and reducing interstitial fibrosis. Notch signaling also plays a regulatory role in adult cardiac injury and in protection of myocardial function after ischemia. The Notch pathway cross-talks with the PI3K/Akt and NF-κB signaling pathways, both of which are well-known factors involved in IPC-induced myocardial protection. We therefore hypothesize that Notch signaling may play a regulatory role in myocardial protection during ischemic preconditioning and hope to find new drug targets to attain the same beneficial effects of Notch signaling without ischemic insults.     

弥可保联合空气压力波治疗糖尿病周围神经病变临床分析

目的探讨弥可保和空气波压力治疗仪联合治疗糖尿病周围神经病变的效果。方法将96例糖尿病周围神经病变患者随机分成两组,对照组单独用弥可保治疗,治疗组弥可保联合空气波压力治疗仪治疗,观察治疗前后自觉症状、腱反射和神经传导速度。结果治疗组总有效率为91．67％,对照组为70．83％,神经传导速度较对照组有显著改善,两组差异有统计学意义（P〈0．05）。结论弥可保联合空气波压力治疗仪治疗糖尿病周围神经病变疗效显著,值得临床推广。     

Sarcoplasmic ATP-sensitive potassium channel blocker HMR1098 protects the ischemic heart: implication of calcium, complex I, reactive oxygen species and mitochondrial ATP-sensitive potassium channel

The aim of this study was to investigate the effects of HMR1098, a selective blocker of sarcolemmal ATP-sensitive potassium channel (sarcK(ATP)), in Langendorff-perfused rat hearts submitted to ischemia and reperfusion. The recovery of heart hemodynamic and mitochondrial function, studied on skinned fibers, was analyzed after 30-min global ischemia followed by 20-min reperfusion. Infarct size was quantified on a regional ischemia model after 2-h reperfusion. We report that the perfusion of 10 microM HMR1098 before ischemia, delays the onset of ischemic contracture, improves recovery of cardiac function upon reperfusion, preserves the mitochondrial architecture, and finally decreases infarct size. This HMR1098-induced cardioprotection is prevented by 1 mM 2-mercaptopropionylglycine, an antioxidant, and by 100 nM nifedipine, an L-type calcium channel blocker. Concomitantly, it is shown that HMR1098 perfusion induces (i) a transient and specific inhibition of the respiratory chain complex I and, (ii) an increase in the averaged intracellular calcium concentration probed by the in situ measurement of indo-1 fluorescence. Finally, all the beneficial effects of HMR1098 were strongly inhibited by 5-hydroxydecanoate and abolished by glibenclamide, two mitoK(ATP) blockers. This study demonstrates that the HMR1098-induced cardioprotection occurs indirectly through extracellular calcium influx, respiratory chain complex inhibition, reactive oxygen species production and mitoK(ATP) opening. Taken together, these data suggest that a functional interaction between sarcK(ATP) and mitoK(ATP) exists in isolated rat heart ischemia model, which is mediated by extracellular calcium influx.