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Previously, we found that a furocoumarin derivative, psoralen (7H-furo[3,2-g][1]benzopyran-7-one), blocked a human Kv1.5 potassium channel (hKv1.5) and has a potential antiarrhythmic effect. In the present study, to develop more potent hKv1.5 blockers or antiarrhythmic drugs, we synthesized ten psoralen derivatives and examined their blocking effects on hKv1.5 stably expressed in Ltk cells. Among the newly synthesized psoralen derivatives, three derivatives (Compounds 5, 9 and 10) showed the open channel-blocking effect. Compound 9 among them was the most potent in blocking hKv1.5. We found that compound 9, one of the psoralen derivatives, inhibited the hKv1.5 current in a concentration-, use- and voltage-dependent manner with an IC50 value of 27.4 +/- 5.1 nM at +60 mV. Compound 9 accelerated the inactivation kinetics of the hKv1.5 channel, slowed the deactivation kinetics of hKv1.5 current resulting in a tail crossover phenomenon. Compound 9 inhibited hKv1.5 current in a use-dependent manner. These results indicate that compound 9, one of psoralen derivatives, acts on hKv1.5 channel as an open channel blocker and is much more potent than psoralen in blocking hKv1.5 channel. If further studies were done, compound 9 might be an ideal antiarrhythmic drug for atrial fibrillation.

Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment, causing pain, impairment, and disability. To identify proteins of CTS comprehensively, a comparative serum analysis of CTS patients and normal control subjects was performed. The two-dimensional electrophoresis patterns of serum obtained from six CTS patients and six normal control subjects were compared. We found 10 proteins that were significantly altered in the serum of CTS patients, among which four were upregulated and six were downregulated. The upregulated spots were identified as Chain A, heat shock 70-kDa protein, 42-kDa ATPase N-terminal domain; glutathione-insulin transhydrogenase (216AA); cAMP-dependent protein kinase inhibitor alpha; and mutant β-globin. The downregulated spots were identified as vitamin D-binding protein (VDBP), fibrinogen gamma chain, apolipoprotein A-IV (ApoA-IV), clusterin, heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1), and one unidentified protein. The information obtained from this proteomic analysis will be very useful in understanding the pathophysiology of CTS and in finding suitable proteins that can serve as new diagnostic biomarkers of CTS.

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Torilin was purified from Torilis japonica (Houtt.) DC., and its effects on a rapidly activating delayed rectifier K+ channel (hKv1.5), cloned from human heart and stably expressed in Ltk- cells, as well as the corresponding K+ current (the ultrarapid delayed rectifier, I(KUR)) were assessed in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, torilin was found to inhibit the hKv1.5 current in time and voltage-dependent manners, with an IC50 value of 2.51+/-0.34 microM at +60 mV. Torilin accelerated the inactivation kinetics of the hKv1.5 channel, and slowed the deactivation kinetics of the hKv1.5 current, resulting in a tail crossover phenomenon. Additionally, torilin inhibited the hKv1.5 current in a use-dependent manner. These results strongly suggest that torilin is a type of open-channel blocker of the hKv1.5 channel.