Tedisamil blocks single large-conductance Ca2+-activated K+ channels in membrane patches from smooth muscle cells of the guinea-pig portal vein

Enzymatically dispersed smooth muscle cells of the guinea-pig portal vein were studied by the patch-clamp technique. They were found to have Ca²⁺-dependent K⁺ channels with the typical properties of the BK channel, i.e. a reversal potential at the calculated equilibrium potential for K⁺ ions, a striking voltage dependence, and a conductance of approximately 200 pS ([K⁺]₀ 50 mM, [K⁺]_i 150 mM, positive patch potentials). Tedisamil, a new bradycardic agent with an inhibitory action on K⁺ currents in heart muscle, reduced the open probability of the BK channels concentration-dependently (1–100 M) when applied at the cytosolic side of membrane inside-out patches. At 100 M [Ca²⁺]_i, the IC₅₀ of tedisamil was 13.8 M (¯x, n=5). Tedisamil increased the frequency of channel closures, and reduced the mean duration of openings from 8 ms to < 1 ms, while the mean duration of closures within bursts (1–2 ms) was not altered. Tedisamil did not affect long closures (> 160 ms) between bursts, either. The mean time of residence of tedisamil at the BK channel was estimated to be 1–2ms. Hence, tedisamil, in comparison to the slow blocker Ba²⁺ and the fast blocker tetraethylammonium, holds the position of an intermediate K⁺ channel blocker.Supported by the Deutsche Forschungsgemeinschaft     

Suppression of charge movement by calcium antagonists is not related to calcium channel block

The calcium channel-inhibiting drugs nitrendipine and diltiazem represent two important classes of organic calcium antagonists. In the present study, the effect of these drugs on calcium currents and charge displacement currents in bullfrog semitendinosus muscle fibers was examined using a vaseline gap voltage clamp. Nitrendipine (10 M) reduced the quantity of charge that moved both during the ON phase (Q_ON) and the OFF phase (Q_OFF) of charge movement. This action appeared to be most selective for Q_ON. However, at this same concentration, nitrendipine had no blocking action on inward calcium currents. In contrast to these findings, diltiazem blocked calcium currents in a concentration-dependent manner, while slightly increasing the quantity of charge moved during Q_ON and Q_OFF. The enhancement of charge movement by diltiazem resulted from two actions. First, diltiazem shifted the voltage-dependence of charge movement to more negative potentials. Second, diltiazem increased the maximum amount of charge moved. (Supported by NIH NS 03178 and HL 07382.)     

Inhibitory activity of a series of coumarins on leukocyte eicosanoid generation

Sixteen plant-derived or synthetic coumarins with different patterns of substitution were tested for their capacity to modify A23187-induced synthesis of leukotriene B₄ and thromboxane B₂ via the 5-lipoxygenase and cyclooxygenase pathways of arachidonate metabolism in rat peritoneal exudate leukocytes. Five of the 16 coumarins inhibited LTB₄ production: all containortho-dihydroxy substitutions (approximate IC₅₀ values 8–100 M). The mechanism is likely to depend upon a combination of the coumarins' iron-chelating and iron ion-reducing abilities, properties which also confer beneficial activities of these compounds as scavengers of reactive oxygen species (Payá et al., Biochem. Pharmacol.44, 205–214 (1992)). Inhibition of the cyclooxygenase pathway was only demonstrated by one compound, 5,7-dihydroxy-4-methylcoumarin, which did not inhibit 5-lipoxygenase, indicating that the cyclooxygenase inhibitory mechanism is different. Similar effects of the active coumarins were obtained using arachidonic acid as substrate for rat leukocyte eicosanoid generation, confirming that they act at the 5-lipoxygenase/cyclooxygenase level. The same profile of activity was also shown when the coumarins were tested against 5-lipoxygenase in human polymorphonuclear neutrophils. Taken together, these antioxidant and anti-eicosanoid properties of coumarins could be exploited for the design of potentially valuable non-toxic anti-inflammatory agents for treating diseases in which eicosanoid generation and the production of reactive oxygen species are involved.     

DIFFERENTIAL SENSITIVITY OF TWO PALMAR SWEAT MEASURES

Two techniques for measuring palmar sweating were tested for their sensitivity to a standard anticholinergic agent. The finger sweat-print and palmar sweatweight methods were compared in a double-blind, crossover study by determining their relative sensitivity in detecting the antisweating effects of 0.5 mg of atropine sulfate. The sweat-print method was significantly superior in detecting drug-induced sweat reduction and hypothesized sex differences.     

Eye Movements and Visually Active Dreams

There are a number of reports suggesting an association between profusion of eye movements and active dreaming. It has however been suggested that this relationship might only be evident in comparisons across the night and would not be evident in comparisons within one REM period. Data from 20 subjects taking placebo, amylobarbitone, and nitrazepam were used to test this. Dream reports were collected from REM awakenings and rated blind as visually active or passive. Eye movement profusion (number of 2 sec epochs) was assessed for each REM period. Correlation between dream content and eye movement was low but significant in comparisons including the whole night, and including data from drug, withdrawal, and placebo conditions. A significant correlation was not consistently obtained, however, when data from each REMP were considered separately. Correlations based on data from non-drug nights only were also small and could have been due to chance effects alone. The low correlations were not explicable solely by poor reliability of content ratings. It is concluded that the relationship between visually active dreaming and eye movement is slight, and may not hold when time of night is adequately controlled.     

妊娠合并癫痫16例临床分析

目的探讨妊娠合并癫痫临床处理。方法回顾性分析16例妊娠合并癫痫孕妇服抗癫痫药情况、癫痫发作频率变化及妊娠结局。结果妊娠合并癫痫发生率0.078%,原发性4例,继发性12例。全身性癫痫发作13例（2例癫痫持续状态）,局部癫痫发作3例。孕期发作频率增加者5例,无变化者6例。孕期新发现单次发作5例。孕期未用抗癫痫药物（AEDs）3例,间断用药1例,连续用药7例,均为单一AEDs治疗。顺产4例,剖宫产10例,人工流产2例。新生儿出生无窒息,平均出生体重2852g,无新生儿出生缺陷,无新生儿死亡。母亲亦无产科并发症发生。2例人工流产孕妇癫痫持续状态、吸入性肺炎死亡,1例智力低下孕妇产后卡马西平中毒昏迷,抢救成功。结论妊娠可诱发并使癫痫发作频率增加。孕期用AEDs可控制癫痫发作。应采用单一AEDs治疗,且应按时监测血浆中AED及叶酸水平。