title: Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm.
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.
authors.affiliation: Department of Molecular Pharmacology & Therapeutics, Loyola University, Chicago, Maywood, IL, USA.
authors.forename: Bharath K
authors.initials: BK
authors.lastname: Mani
authors.forename: James
authors.initials: J
authors.lastname: O'Dowd
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.forename: Lioubov I
authors.initials: LI
authors.lastname: Brueggemann
authors.forename: Masey
authors.initials: M
authors.lastname: Ross
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Byron
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002219:Carbamates / Q000494:pharmacology; D000068579:Celecoxib; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009213:Myography; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D019332:Endothelin-1; D051656:KCNQ Potassium Channels; D049990:Membrane Transport Modulators; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; C101866:ezogabine; D012701:Serotonin; D000068579:Celecoxib