Chronic heart failure slows late sodium current in human and canine ventricular myocytes: implications for repolarization variability

BACKGROUND: Late Na(+) current (I(NaL)) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na(+) channels, which could contribute to these abnormalities. AIMS: To test how altered gating affects I(NaL) time course, Na(+) influx, and action potential (AP) repolarization. METHODS: I(NaL) and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization. RESULTS: I(NaL) decay was slower and I(NaL) density was greater in failing hearts than in normal hearts at 24 degrees C (human hearts: tau=659+/-16 vs. 529+/-21 ms; n=16 and 4 hearts, respectively; mean+/-SEM; p<0.002; dog hearts: 561+/-13 vs. 420+/-17 ms; and 0.307+/-0.014 vs. 0.235+/-0.019 pA/pF; n=25 and 14 hearts, respectively; p<0.005) and at 37 degrees C this difference tended to increase. These I(NaL) changes resulted in much greater (53.6%) total Na(+) influx in failing cardiomyocytes. I(NaL) was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC(50)=62 nM) or tetrodotoxin (IC(50)=1.2 muM), tested in dogs. A 50% I(NaL) inhibition by toxins or passing current opposite to I(NaL), decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes. CONCLUSIONS: Chronic HF leads to larger and slower I(NaL) generated mainly by the cardiac-type Na(+) channel isoform, contributing to larger Na(+) influx and AP duration variability. Interventions designed to reduce/normalize I(NaL) represent a potential cardioprotective mechanism in HF via reduction of related Na(+) and Ca(2+) overload and improvement of repolarization.     

Tool use and related errors in ideational apraxia: the quantitative simulation of patient error profiles

The behaviour of ideational apraxic patients on simple tasks involving multiple objects is typically marked by a variety of errors. While some of these errors concern the sequential organisation of action through time, many relate to the misuse of, or failure to use, necessary or appropriate tools. In this paper we apply the computational model of Cooper and Shallice (2000) to five standard multiple object tasks used in clinical assessment and demonstrate how, when lesioned, the model can account for the error profiles of two ideational apraxic patients discussed by Rumiati et al. (2001). Application of the model to the multiple object tasks demonstrates the generality of the model, while the account of the error profiles extends previous work (Cooper et al., 2005) in which ideational apraxia was argued to arise from a generalised disturbance of object representations that are held to trigger action schemas.     

Contribution of reference electrode to the compound muscle action potential

In compound muscle action potential (CMAP) recording, the contribution by the reference electrode is considered to be much smaller than that of the active electrode. We tested this assumption by making quantitative measurements of the signals recorded individually by the active and reference electrodes. In the thenar (median nerve) and extensor digitorum brevis (peroneal nerve) muscles, the reference electrode did contribute less. In the hypothenar muscle (ulnar nerve), however, the signals recorded by active and reference electrodes were of similar amplitude. In tibial nerve conduction studies (NCS), the CMAP from the abductor hallucis (AH) muscle was recorded mainly by the reference electrode; the large-amplitude signal recorded by the reference electrode is attributed to volume-conducted activity from other muscles stimulated during the study. The onset latency of the potential recorded by the active and reference electrodes was similar despite significantly different distances from the stimulating site. Hence, the merits of using anatomic landmarks for defining the distal stimulation site are assessed. When the reference electrode makes a large contribution, the CMAP amplitude may not decrease commensurate with any wasting of the muscle under the active recording electrode, and the need to use another muscle for recording the CMAP for that nerve should be considered.     

中药了哥王研究进展

目的对中药了哥王的化学成分和药理作用等方面研究做一系统概述。方法通过系统查阅国内外发表的30余篇文献,对其化学成分和药理作用等方面研究进行了总结归纳。结果了哥王主要含有香豆素类、黄酮类、木脂素类等多种化学成分。具有抗菌、抗病毒、抗炎、抗癌等药理作用。临床用于上呼吸道感染、肝炎、乳腺炎等病症的治疗。结论本文旨在为中药了哥王的进一步开发利用提供一定参考。     

鬼针草总黄酮的化学成分及药理作用研究进展

鬼针草是我国民间常用的中药,全国大部分地区均有分布。鬼针草总黄酮（total flavonoids of Bidens bipinnata L．,TFB）是鬼针草的主要有效成分,包括槲皮素、金丝桃苷、槲皮素-7-O-鼠李糖苷、6,7,3’,4’-四羟基橙酮、2’,3’,4’,3,4-五羟基查耳酮（奥卡宁）、木犀草素等。本文综述了近年来鬼针草总黄酮的提取分离、含量测定及药理作用等方面的研究,特别是在抗肝纤维化方面研究取得的进展。     

Addictive evaluation of cholic acid-verticinone ester,a potential cough therapeutic agent with agonist action of opioid receptor

Aim:

The purpose of this work was to search for potential drugs with potent antitussive and expectorant activities as well as a low toxicity, but without addictive properties. Cholic acid-verticinone ester (CA-Ver) was synthesized based on the clearly elucidated antitussive and expectorant activities of verticinone in bulbs of Fritillaria and different bile acids in Snake Bile. In our previous study, CA-Ver showed a much more potent activity than codeine phosphate. This study was carried out to investigate the central antitussive mechanism and the addictive evaluation of CA-Ver.

Methods:

Testing on a capsaicin-induced cough model of mice pretreated with naloxone, a non-selective opioid receptor antagonist, was performed for the observation of CA-Ver''s central antitussive mechanism. We then took naloxone-induced withdrawal tests of mice for the judgment of CA-Ver''s addiction. Lastly, we determined the opioid dependence of CA-Ver in the guinea pig ileum.

Results:

The test on the capsaicin-induced cough model showed that naloxone could block the antitussive effect of CA-Ver, suggesting the antitussive mechanism of CA-Ver was related to the central opioid receptors. The naloxone-urged withdrawal tests of the mice showed that CA-Ver was not addictive, and the test of the opioid dependence in the guinea pig ileum showed that CA-Ver had no withdrawal response.

Conclusion:

These findings suggested that CA-Ver deserved attention for its potent antitussive effects related to the central opioid receptors, but without addiction, and had a good development perspective.     

甲氧沙林脂质体凝胶的毒理学试验

目的：对甲氧沙林脂质体（LMOP）凝胶的毒理进行考察,以评价其生物安全性。方法：以豚鼠为实验动物,观察豚鼠完整皮肤及破损皮肤短时间接触LMOP凝胶后所产生的毒性反应情况以及单次与多次接触LMOP凝胶后所产生的局部刺激反应,并通过动物皮肤重复接触LMOP凝胶后,观察机体免疫系统在动物皮肤上的反应。结果：LMOP在豚鼠完整或破损皮肤局部均无明显刺激性及毒性,多次使用LMOP后,全身也无明显的毒性反应。结论：LMOP具有较高的皮肤应用安全性,值得进一步研究。     

Pharmacological effects of saw palmetto extract in the lower urinary tract

Saw palmetto extract （SPE）, an extract from the ripe berries of the American dwarf palm, has been widely used as a therapeutic remedy for urinary dysfunction due to benign prostatic hyperplasia （BPH） in Europe. Numerous mechanisms of action have been proposed for SPE, including the inhibition of 5a-reductase. Today, al-adrenoceptor antagonists and muscarinic cholinoceptor antagonists are commonly used in the treatment of men with voiding symptoms secondary to BPH. The improvement of voiding symptoms in patients taking SPE may arise from its binding to pharmacologically relevant receptors in the lower urinary tract, such as al-adrenoceptors, muscarinic cholinoceptors, 1,4-dihyropyridine receptors and vanilloid receptors. Furthermore, oral administration of SPE has been shown to attenuate the up-regulation of α1-adrenoceptors in the rat prostate induced by testosterone. Thus, SPE at clinically relevant doses may exert a direct effect on the pharmacological receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and an overactive bladder. SPE does not have interactions with co-administered drugs or serious adverse events in blood biochemical parameters, suggestive of its relative safety, even with long-term intake. Clinical trials （placebo-controlled and active-controlled trials） of SPE conducted in men with BPH were also reviewed. This review should contribute to the understanding of the pharmacological effects of SPE in the treatment of patients with BPH and associated lower urinary tract symptoms （LUTS）.     

The protective effect of genistein postconditioning on hypoxia/ reoxygenation-induced injury in human gastric epithelial cells

Aim： The aim of this study was to investigate the protective effect of genistein postconditioning on hypoxia/reoxygenation- induced injury in human gastric epithelial cells and to begin a tentative discussion on the mechanism behind this protection. Methods： A model of hypoxia/reoxygenation-induced injury was established in the human gastric epithelial cell line （GES-1）. All cells in our present study were randomly divided into five groups： a normal control group （N）, a hypoxia/ reoxygenation group （H/R）, a genistein postconditioning group （GP）, a capsazepine＋genistein postconditioning group （C＋GP） and a DMSO vehicle postconditioning group （DM）. The methods used included MTT assays to test cell viability, flow cytometric analyses to quantify the percentage of cell apoptosis, Western blot analyses to measure the protein expression of calcitonin gene-related peptide （CGRP）, Bcl-2, and Bax, and immunocytochemistry assays to detect the expression of CGRP in each group. Results： The MTT assays indicated that the cell viabilities of the groups were 100.0%±0%, 51.4%±4.1%, 66.7%±2.0%, 56.1%±2.8%, and 50.7%±2.4%, respectively. Compared with the H/R group, the viability of the GP group was significantly increased （P〈0.01）. Flow cytometric analysis showed that the cell apoptosis percentage of each group was 2.28%±0.44%, 12.17%±2.15%, 5.40%±1.22%, 10.43%±1.37%, and 11.02%±2.19%, respectively. Western blot analysis demonstrated that CGRP, Bcl-2, and Bax were expressed in normal human gastric epithelial cells. Compared with the H/R group, the GP group exhibited increased expression of CGRP and Bcl-2 and decreased expression of Bax. Immunocytochemistry assays indicated that the number of CGRP-positive cells in the GP group was significantly increased. Conclusion： Genistein postconditioning has a protective effect on hypoxia/reoxygenation-induced injury in human gastric epithelial ceils. The mechanism by which genistein exerts this protection may be via activation of cell     

Effect of tacrolimus derivatives on immunosuppression

In this study, the effects of the FK506-mPEG on immune cell activity, skin grafting rejection, and Freund’s complete adjuvant arthritis were investigated. The proliferation of T cells was inhibited with increase with the FK506 and FK506-mPEG concentrations. FK506 and FK506-mPEG at concentrations between 0.01 nM and 1000 nM had very similar effects on the proliferation of the T cells. On the other hand, in the case of the proliferation of T cells by calcium ionophore A23187 (1 μM), when the FK506-mPEG concentration was increased from 0.01 to 1000 mM, the proliferation was decreased from 90.8 to 40.3%. This was 1.8-fold higher than that of paramethoxyamphetamine (PMA). The inhibitory effect of FK506-mPEG on mast cell proliferation was higher than that of FK506. When B cells were cultured for 7 days in basal medium with no pokeweed mitogen (PWM), the IgG production was 156.2 ng/mL. On the other hand, in the case of the same treatment with 0.25% of PWM, it was 876.4 ng/mL. This is about 5.6-fold higher than with no PWM. These results show that FK506-mPEG may be practically applicable as a prodrug for the immunosuppressant FK506.