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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 13, 2008; DOI: 10.1124/jpet.107.135764

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Received for publication December 26, 2007.
Revised January 25, 2008.
Accepted for publication February 12, 2008.

Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction: based on studies in single cells, pressurized arteries and in vivo measurements of mesenteric vascular resistance

Alexander R Mackie 1, Lioubov I Brueggemann 2, Kyle K Henderson 2, Aaron J Shiels 2, Leanne L Cribbs 2, Karie E Scrogin 2, Kenneth L. Byron 1*

1 Loyola University of Chicago 2 Loyola University Chicago

* Address correspondence to: E-mail: kbyron{at}lumc.edu

Abstract

Pressor effects of the vasoconstrictor hormone arginine vasopressin (AVP), observed when systemic AVP concentrations are less than 100 pM, are important for the physiological maintenance of blood pressure and are also the basis for therapeutic use of vasopressin to restore blood pressure in hypotensive patients. However, the mechanisms by which circulating AVP induces arterial constriction are unclear. We examined the novel hypothesis that KCNQ potassium channels mediate the physiological vasoconstrictor actions of AVP. Reverse transcriptase polymerase chain reaction revealed expression of KCNQ1, KCNQ4 and KCNQ5 in rat mesenteric artery smooth muscle cells (MASMCs). Whole-cell perforated patch recordings of voltage-sensitive K+ (Kv) currents in freshly isolated MASMCs revealed KCNQ currents that were electrophysiologically and pharmacologically distinct from other Kv currents. Suppression of KCNQ currents by AVP (100 pM) was associated with significant membrane depolarization and was abolished by the protein kinase C (PKC) inhibitor calphostin C (250 nM). The KCNQ channel blocker linopirdine (10 µM) inhibited KCNQ currents in MASMCs and induced constriction of isolated rat mesenteric arteries. The vasoconstrictor responses were not additive when combined with 30 pM AVP and were prevented by the L-type Ca2+ channel blocker verapamil. Flupirtine significantly enhanced KCNQ currents and reversed constrictor responses to 30 pM AVP. In vivo, intravenous administration of linopirdine induced a dose-dependent increase in mesenteric artery resistance and blood pressure, whereas flupirtine had the opposite effects. We conclude that physiological concentrations of AVP induce mesenteric artery constriction via PKC-dependent suppression of KCNQ currents and L-type Ca2+ channel activation in MASMCs.


Key words: ion channels, m-current, membrane potential, pressure myography, vascular resistance, vasoactive hormones




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