Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm

Bharath K. Mani, James O'Dowd, Lalit Kumar, Lioubov I. Brueggemann, Masey Ross, Kenneth L. Byron

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is characterized by prolonged severe constriction of the basilar artery, which often leads to ischemic brain damage. Locally elevated concentrations of spasmogenic substances induce persistent depolarization of myocytes in the basilar artery, leading to continuous influx of calcium (Ca) through voltage-sensitive Ca channels and myocyte contraction. Potassium (K) channel openers may have therapeutic utility to oppose membrane depolarization, dilate the arteries, and reduce ischemia. Here, we examined the involvement of vascular Kv7 K channels in the pathogenesis of cerebral vasospasm and tested whether Kv7 channel openers are effective therapeutic agents in a rat model of SAH. Patch-clamp experiments revealed that 3 different spasmogens (serotonin, endothelin, and vasopressin) suppressed Kv7 currents and depolarized freshly isolated rat basilar artery myocytes. These effects were significantly reduced in the presence of a Kv7 channel opener, retigabine. Retigabine (10 μM) also significantly blocked L-type Ca channels, reducing peak inward currents by >50%. In the presence of a selective Kv7 channel blocker, XE991, the spasmogens did not produce additive constriction responses measured using pressure myography. Kv7 channel openers (retigabine or celecoxib) significantly attenuated basilar artery spasm in rats with experimentally induced SAH. In conclusion, we identify Kv7 channels as common targets of vasoconstrictor spasmogens and as candidates for therapeutic intervention for cerebral vasospasm.

Original languageEnglish (US)
Pages (from-to)51-62
Number of pages12
JournalJournal of Cardiovascular Pharmacology
Volume61
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • basilar artery
  • celecoxib
  • cerebral vasospasm
  • membrane depolarization
  • potassium channel
  • retigabine

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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