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NEUROPHARMACOLOGY

KW-7158 [(2S)-(+)-3,3,3-Trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] Enhances A-Type K⁺ Currents in Neurons of the Dorsal Root Ganglion of the Adult Rat

Departments of Pharmacology (A.S., N.Y., W.C.d.G.) and Urology (N.Y.), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania

Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K⁺ currents at concentrations ranging from 50 nM to 1 µM (20–50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5- to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 µM) or substance P (0.5 µM) in phasic firing DRG neurons. Above 1 µM, KW-7158 elicited a smaller enhancement of A-type K⁺ currents and in high concentrations inhibited the currents. Tetraethylammonium (5–60 mM) and verapamil (50 µM), which block noninactivating K⁺ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K⁺ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K⁺ currents in DRG neurons. Because A-type K⁺ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

Address correspondence to: Dr. Adrian Sculptoreanu, Department of Pharmacology, E1304 Biomedical Science Tower, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261. E-mail: ads5{at}pitt.edu

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