New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

Mitochondrial ATP-sensitive K⁺ (mitoK_ATP) and Ca²⁺-activated K⁺ (mitoK_Ca) channels exist in cardiac myocytes, and they play key roles in cardioprotection. We have recently reported that K⁺ influx through mitoK_ATP or mitoK_Ca channels occurs independently of each other and confers cardioprotection in a similar manner. Activation of mitoK_ATP channel is augmented by protein kinase C (PKC), whereas mitoK_Ca channel is activated by protein kinase A (PKA). However, phosphatidylinositol 3-kinase (PI3-K) is linked to neither mitoK_ATP nor mitoK_Ca channels. We have demonstrated that bioactive substances modulate the opening of mitoK_ATP channels via a PKC-dependent pathway or opening of mitoK_Ca channels via a PKA-dependent pathway and thereby protecting the heart from ischemia/reperfusion injury. Several endogenous substances such as adenosine and bradykinin can reduce infarct size by activation of mitoK_ATP channels in a PKC-dependent manner. Adrenomedullin, a potent vasodilator peptide, potentiates the opening of mitoK_Ca channels by PKA activation. Treatment with adrenomedullin prior to ischemia results in the reduction of infarct size via a PKA-mediated activation of mitoK_Ca channels. Thus, some endogenous substances confer cardioprotection via PKA- or PKC-mediated activation of mitoK_ATP or mitoK_Ca channels.     

Cardioprotective activity of alcoholic extract of Tinospora cordifolia （Willd.） Miers in calcium chloride-induced cardiac arrhythmia in rats

The present study investigated the antiarrhythmic activity of alcoholic extract of Tinospora cordifolia (T.cordifolia) in CaCl 2 induced arrhythmia.CaCl 2 (25 mg/kg) was administered by intravenous infusion (iv) to produce arrhythmia in rats.The animals were then treated with T.cordifolia extract (150,250,and 450 mg/kg) and verapamil (5 mg/kg,iv).Lead II electrocardiogram was monitored.Plasma calcium,sodium and potassium levels were measured.In CaCl 2 induced arrhythmia,heart rate was decreased by 41.10%,T....     

CALCITONIN GENE-RELATED PEPTIDE MEDIATES THE CARDIOPROTECTIVE EFFECTS OF RUTAECARPINE AGAINST ISCHAEMIA–REPERFUSION INJURY IN SPONTANEOUSLY HYPERTENSIVE RATS

• 1 It has been shown that calcitonin gene‐related peptide (CGRP) plays an important role in mediating the cardioprotection exerted by rutaecarpine in normal animals. The aim of the present study was to determine whether rutaecarpine is able to decrease the susceptibility of hypertensive animals to ischaemia–reperfusion injury by stimulating CGRP release.
• 2 Spontaneously hypertensive rats (SHR) were pretreated with rutaecarpine (20 or 40 mg/kg per day, i.g.) for 18 days and then the heart and thoracic aorta were isolated for cardiac function and vascular relaxation analysis. Blood samples and coronary effluent were collected to measure CGRP levels and creatine kinase activity, respectively. The effect of 10 or 30 µmol/L rutaecarpine on CGRP release was also examined in isolated aortic rings set up in a homeothermal organ bath.
• 3 Rutaecarpine treatment resulted in a hypotensive effect in SHR concomitant with increases in plasma CGRP levels. In addition, rutaecarpine significantly stimulated the release of CGRP from aortic rings. Twenty minutes ischaemia and 30 min reperfusion resulted in a marked decrease in myocardial function and a significant increase in the release of creatine kinase in normal control (Wistar‐Kyoto) rats, an effect that was exacerbated in SHR. Similarly, the decreased vasodilator response to acetylcholine (3 ? 10^?9 to 10^?6 mol/L) in isolated aortic rings from Wistar‐Kyoto rats was also aggravated in SHR. Both cardiac function and vasodilator responses were significantly improved in SHR after pretreatment with rutaecarpine.
• 4 The results of the present study suggest that the increased cardiac susceptibility to ischaemia–reperfusion injury in SHR is related to decreased plasma CGRP levels and that antihypertensive therapy with rutaecarpine reverses cardiac susceptibility to reperfusion injury by stimulating CGRP release.

     

地龙化学成分及药理活性研究进展

地龙是传统中药,具有清热定惊、通络、平喘等功效,临床常用于治疗高热神昏、肺热咳喘、半身不遂等。地龙所含化学成分众多,其中氨基酸类、多肽类、核苷类和有机酸等类化合物为其主要活性成分。现代药理研究表明地龙具有抗炎、抗血栓、心脏保护、抗肿瘤和改善呼吸系统功能等作用。总结了近年来国内外有关地龙化学成分、药理活性相关文献,对其研究进展进行综述,为地龙的药物开发及临床应用提供依据。     

Cardioprotection: spotlight on PKG

Classical ischaemic preconditioning, delayed or second window preconditioning and postconditioning are forms of cardioprotection that are dependent on cell surface receptors, intracellular signalling molecules and kinases that ultimately block formation of the mitochondrial permeability transition. The latter is presumed to cause myocardial necrosis as well as apoptosis, so prevention of its formation upon resumption of perfusion after a prolonged coronary occlusion should be cardioprotective. In all of these forms of cardioprotection, formation of cGMP and activation of protein kinase G (PKG) are recognized to be key steps in the signal transduction pathway. Burley et al. highlight the roles of cGMP and PKG in their comprehensive review. They describe the basic biology of PKG and emphasize its compartmentalization, which may be responsible for the frustration induced by assays for PKG in whole cell lysates and for the spurious conclusions about the role of PKG in cardioprotection. This review will be useful to both the novice and the seasoned investigator.     

Sevoflurane-induced cardioprotection depends on PKC-alpha activation via production of reactive oxygen species

BACKGROUND: We previously demonstrated the involvement of the Ca2+-independent protein kinase C-delta (PKC-delta) isoform in sevoflurane-induced cardioprotection against ischaemia and reperfusion (I/R) injury. Since sevoflurane is known to modulate myocardial Ca2+-handling directly, in this study we investigated the role of the Ca2+-dependent PKC-alpha isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K+ (mitoK+(ATP)) channels, and PKC-delta. METHODS: Preconditioned (15 min 3.8 vol% sevoflurane) isolated rat right ventricular trabeculae were subjected to I/R, consisting of 40 min superfusion with hypoxic, glucose-free buffer, followed by normoxic glucose-containing buffer for 60 min. After reperfusion, contractile recovery was expressed as percentage of force development before I/R. The role of PKC-alpha, ROS, mitoK+(ATP) channels, and PKC-delta was established using the following pharmacological inhibitors: Go6976 (GO; 50 nM), n-(2-mercaptopropionyl)-glycine (MPG; 300 microM), 5-hydroxydecanoic acid sodium (5HD; 100 microM), and rottlerin (ROT; 1 microM). RESULTS: Preconditioning of trabeculae with sevoflurane improved contractile recovery after I/R [65 (3)% (I/R + SEVO) vs 47 (3)% (I/R); n = 8; P < 0.05]. This cardioprotective effect was attenuated in trabeculae treated with GO [42 (4)% (I/R + SEVO + GO); P > 0.05 vs (I/R)]. In sevoflurane-treated trabeculae, PKC-alpha translocated towards mitochondria, as shown by immunofluorescent co-localization analysis. GO and MPG, but not 5HD or ROT, abolished this translocation. CONCLUSIONS: Sevoflurane improves post-ischaemic contractile recovery via activation of PKC-alpha. ROS production, but not opening of mitoK+(ATP) channels, precedes PKC-alpha translocation towards mitochondria. This study shows the involvement of Ca2+-dependent PKC-alpha in addition to the well-established role of Ca2+-independent PKC isoforms in sevoflurane-induced cardioprotection.     

新型NO供体SP/W-5186在兔心肌缺血/再灌注损伤中的作用和机制

目的：研究一种结构中含有半胱氨酸的新型一氧化氮供体ＳＰ／Ｗ＝－５１８６，在新西兰兔缺血／再灌注心肌损伤中的作用和机制。方法：兔缺血４５ｍｉｎ继之再灌注１８０ｍｉｎ。再灌注前５ｍｉｎ，通过静脉单剂量给予低剂量（０．３μｍｏｌ／ｋｇ）或高剂量（１μｍｏｌ／ｋｇ）的ＳＰ／Ｗ０５１８６。结果：给予０．３μｊｏｌ／ｋｇＷＰ／Ｗ０－５１８６对平均动脉压、心率等心功能指标没有影响，可显著地降低血小板聚集，减少白     

Volatile anaesthetics and cardioprotection – lessons from animal studies

Volatile anaesthetics emerged as important cardioprotective agents in both animal models of ischaemia/reperfusion injury and humans with coronary artery disease. Their administration before a prolonged ischaemic episode is known as anaesthetic preconditioning, whereas when given at the very onset of reperfusion, the strategy is termed anaesthetic postconditioning. Both types of anaesthetic conditioning reduce, albeit not to the same degree, the extent of myocardial injury. They share similar, albeit not identical, intracellular signal transduction pathways with their widely investigated counterparts, ischaemic pre‐ and postconditioning. Despite a wealth of preclinical evidence for cardioprotection for anaesthetic conditioning strategies, their translation into clinical therapy has been rather disappointing. This review highlights the major findings on the cardioprotective effects of volatile anaesthetics in experimental settings. It explores hypotheses that may explain the lack of efficacy observed in several past clinical studies paving the way for future preclinical and translational studies.