Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 155, Issue 1, Pages 62-72Publisher
WILEY
DOI: 10.1038/bjp.2008.231
Keywords
KCNQ; K(v)7; retigabine; XE991; vascular smooth muscle; RT-PCR; immunocytochemistry; isometric tension
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Funding
- British Heart Foundation [PG/O3/085/15747]
- Deutsche Forschungsgemeinschaft
- British Heart Foundation Intermediate Research Fellowship [FS/04/052]
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Background and purpose: This study investigated the functional and electrophysiological effects of the K(v)7 channel activator, retigabine, on murine portal vein smooth muscle. Experimental approach: KCNQ gene expression was determined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemical experiments. Whole cell voltage clamp and current clamp were performed on isolated myocytes from murine portal vein. Isometric tension recordings were performed on whole portal veins. K+ currents generated by KCNQ4 and KCNQ5 expression were recorded by two-electrode voltage clamp in Xenopus oocytes. Key results: KCNQ1, 4 and 5 were expressed in mRNA derived from murine portal vein, either as whole tissue or isolated myocytes. K(v)7.1 and K(v)7.4 proteins were identified in the cell membranes of myocytes by immunocytochemistry. Retigabine (2-20 mu M) suppressed spontaneous contractions in whole portal veins, hyperpolarized the membrane potential and augmented potassium currents at -20 mV. At more depolarized potentials, retigabine and flupirtine, decreased potassium currents. Both effects of retigabine were prevented by prior application of the K(v)7 blocker XE991 (10 mu M). Recombinant KCNQ 4 or 5 channels were only activated by retigabine or flupirtine. Conclusions and implications: The K(v)7 channel activators retigabine and flupirtine have bimodal effects on vascular potassium currents, which are not seen with recombinant KCNQ channels. These results provide support for KCNQ4- or KCNQ5-encoded channels having an important functional impact in the vasculature.
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