Pharmacology of KB‐R7943: A Na+–Ca2+ exchange inhibitor

The Na⁺–Ca²⁺ exchange (NCX) system plays a pivotal role in regulating intracellular Ca²⁺ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca²⁺‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.     

Activation of guinea pig eosinophil respiratory burst by leukotriene B4: role of protein kinase C

Leukotriene B4 (LTB4) and the protein kinase C activator, 4-beta-phorbol dibutyrate (PDBu), both induced a pronounced and concentration-dependent stimulation of hydrogen peroxide (H2O2) generation by purified guinea pig peritoneal eosinophils in the concentration range 1 nM-1 microM. The LTB4 response was inhibited competitively by the specific LTB4 receptor antagonist, U-75302, with a KB of 25 nM, while the concentration-response curves for both stimuli were shifted rightwards (3.8-fold and 2.8-fold for LTB4 and PDBu, respectively) by the competitive protein kinase C inhibitor, 1-O-hexadecyl-2-O-methylglycerol at a concentration of 300 microM. LTB4 appears, therefore, to induce respiratory burst in eosinophils via a receptor-mediated mechanism involving protein kinase C.     

Acute toxicity of two pyrethroids,permethrin, and cypermethrin in neonatal and adult rats

The present study aims specifically at obtaining a comparison of the acute toxicity of cypermethrin (CY), a type I pyrethroid, and permethrin (PERM), a type II pyrethroid, administered orally as a single dose to neonatal and adult rats, and at assessing the importance of pyrethroid biotransformation in CY and PERM toxicity through use of drug metabolism inhibitors. Our experiments show that CY is more toxic than PERM to adult and neonatal rats. The sensitivity of neonatal rats both to CY and to PERM toxicity is higher, the younger the animals. CY is much more toxic than PERM in the neonatal rat, compared with the adult. In rats aged 8, 16, and 21 days, pretreatment with piperonil butoxide (PB), a monooxygenase inhibitor, or with tri-o-tolyl phosphate (TOTP), an esterase inhibitor, does not produce significant variations in the lethal effects of CY and PERM. Instead, in the adult rats, a significant increase in CY (X²=5.97;p<0.05) and PERM (X²=4.37;p<0.05) mortality occurred in rats pretreated with esterase inhibitors, whereas no increase in CY and PERM toxicity was found in adult animals pretreated with monooxygenase inhibitor. It was concluded that the higher level of sensitivity of the neonate rat to pyrethroid toxicity is probably due to incomplete development of the enzymes which catalyze the metabolism of pyrethroids in the liver of young animals. It is suggested that ester hydrolysis is an important pyrethroids detoxification reaction in the adult rat.     

氨基胍对大鼠脊髓压迫伤后后肢运动功能的影响

目的观察诱导型一氧化氮合酶抑制剂-氨基胍(AG)对大鼠脊髓损伤后运动功能的影响。方法大鼠脊髓压迫伤后给予AG进行治疗,24 h后用分光光度法测定脊髓组织中一氧化氮(NO)含量和NOS活性;72 h后用流式细胞仪检测神经细胞凋亡情况;4周后用电生理和动物行为学等指标评价运动功能的恢复情况。以正常大鼠和损伤未治大鼠为对照。结果AG可以抑制组织中的NO含量和NOS活性,同时降低神经细胞的凋亡比率,提高动物后肢运动功能评分,恢复运动诱发电位的振幅和潜伏期,与对照及损伤未治大鼠相比均有显著差异(P<0.05)。结论脊髓损伤后应用NOS抑制剂可以使伤后运动功能得到改善,提示iNOS活性变化可能对脊髓损伤的恢复更具决定作用,其作用机制与抑制伤后细胞凋亡有关。     

人肺癌细胞转录因子--C/EBP和HMG样蛋白的EMSA检测

目的：检测人肺癌细胞中是否存在与Na^ /H^ 交换蛋白-1（NHE-1）基因转录相关的重要转录因子--C/EBP和HMG样蛋白。方法：采用电泳迁移率改变分析法（EMSA）检测人肺癌细胞株核蛋白中C/EBP和HMG样蛋白的表达及其水平。结果：EMSA检测到A549细胞和转染NHE-1反义载体的A549细胞均有转录因子C/EBP和HMG样蛋白的表达，且后者表达水平高于前者；采用50倍未标记的片段能完全抑制相应转录因子与^32P标记的相同片段的结合。结论：A549细胞核蛋白中存在能与C/EBP结合序列和Poly(dA：dT)区结合的转录因子，即C/EBP和HMG样蛋白，后者的表达水平高于前者。特异性竞争抑制试验表明外源性特异DNA片段能抑制相同片段与转录因子的结合。     

来流温度不均匀对叉流换热器性能的影响

对来流温度不均匀叉流换热器,本文进行了熵产生和(火用)效率的数值分析。结果表明:①在相同的传热单元数和热容量比值下,对应于换热效果最好的来流温度分布,其熵产生单元数最小,(火用)效率最高。②在给定的条件下,换热器的(火用)效率并不是随传热单元数的增加而单调增加,而是存在一个极大值,它所对应的传热单元数要小于有效度ε_(max)对应的传热单元数。③熵产生单元数也并不是随传热单元数的增加而单调减少,而是有时单调增加,有时有极大值。并对以上现象作了一些物理机理的分析和讨论。     

Deleterious effect of exogenous angiotensin-I on the extent of regional ischaemia and its inhibition by captopril

The endogenous activity of the local renin-angiotensin system(RAS) and the anti-ischaemic properties of captopril were investigatedin electrically driven rabbit Langendorff hearts (constant pressure:70 cmH₂O, Tyrode solution, Ca²⁺ 1.8 mmol.l^–1). Cumulativeconcentration-response curves showed no significant difference(P>0.05) between the reduction of the global coronary flow(CF) by exogenous angiotensin-I or angiotensin-II (EC₅₀ = 10^–10mol.l^–1). It is concluded that the local RAS in isolatedrabbit hearts is highly sensitive, whereas its endogenous activityis very low due to very low endogenous angiotensin-I content.Myocardial ischaemia (MI) was induced by the occlusion of aleft coronary artery branch and MI was quantified from NADHsurface fluorescence photography. MI was significantly enlarged(+35%) (P <0.05) by exogenous angiotensin-I (6x10^–9mol.l^–1). The reduction in CF and the increment in MIby angiotensin-I could be completely prevented by adding captoprilat a low concentration (10^–6 mol.l^–1) to the perfusionbuffer. In the absence of exogenous angiotensin-I, captoprilalone (10^–6 mol.l^–1) neither significantly enhancedCF (P >0.05), nor diminished MI (P >0.05), supportingthe finding of very low endogenous activity of tile local RASin this model. We, moreover, conclude that at a low concentration(10^–6 mol.l^–1) captopril does not possess directcardioprotective properties independent of its ACE inhibitingaction.     

Effects of trapidil-derivatives on calcium channel currents in isolated ventricular cells from mice

Summary A single glass micropipette voltage clamp technique with intracellular dialysis was used to study the effects of the trapidil derivatives AR 12–456 and AR 12–463 on Ca channel currents carried by Bat+ in isolated ventricular cells from mice hearts. Inspite of a more potent inhibition of the cAMP phosphodiesterase from heart (Bartel et al. 1985) a reversible Ca channel blocking action of both compounds could be observed. The concentration of half maximal block was calculated to about 50 mol/l for both derivatives tested. Neither a shift in the current-voltage relationships nor a significant change in the potential for half maximal activation was found. The maximal Ba²⁺ -conductance was reduced. The steady state inactivation was shifted towards more negative potentials by application of 100 mol/l AR 12–463. The decay of the Ba currents was accelerated in the range of the applied test potentials between –20 and +20 mV. It is concluded that the new trapidil derivatives with more potent inhibitory action on cardiac phosphodiesterase than trapidil can block myocardial Ca channels. Send offprint requests to B. Nilius     

Selective inhibition of MAO-A,not MAO-B,results in antidepressant-like effects on DRL 72-s behavior

The effects of monoamine oxidase inhibitors (MAOIs) that selectively inhibit the MAO-A or MAO-B forms of MAO were studied in rats performing under a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Clorgyline and CGP11305A, irreversible and reversible MAO-A inhibitors, respectively, increased the reinforcement rate, decreased the response rate, and enhanced temporal discrimination. The irreversible MAO-B inhibitor (–)-deprenyl did not produce similar effects. Pargyline did not increase the reinforcement rate at low doses that selectively inhibit MAO-B, but did increase the reinforcement rate at doses that inhibit MAO-A by more than 90%. The present results are in accord with clinical data demonstrating that MAO-A inhibitors are effective therapeutic agents in treating depression while MAO-B inhibitors are of questionable antidepressant efficacy. The present findings provide further evidence that the DRL 72-s schedule may be useful both as a screen for identifying new antidepressants and for investigating the neurochemical effects of antidepressant drugs that are responsible for their therapeutic effects.