Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery
Article first published online: 22 AUG 2011
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 164, Issue 2, pages 237–249, September 2011
How to Cite
Mani, B. K., Brueggemann, L. I., Cribbs, L. L. and Byron, K. L. (2011), Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery. British Journal of Pharmacology, 164: 237–249. doi: 10.1111/j.1476-5381.2011.01273.x
- Issue published online: 22 AUG 2011
- Article first published online: 22 AUG 2011
- Accepted manuscript online: 16 FEB 2011 11:49PM EST
- Received; 3 September 2010; Revised; 3 December 2010; Accepted; 12 January 2011
- cerebral vasospasm;
- basilar artery;
- membrane voltage;
- potassium channel;
BACKGROUND AND PURPOSE Cerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (Kv7) potassium channels in rat basilar artery myocytes, and determined the efficacy of Kv7 channel activators in relieving spasmogen-induced basilar artery constriction.
EXPERIMENTAL APPROACH Expression and function of Kv7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to Kv7 channel modulators were studied in intact artery segments using pressure myography.
KEY RESULTS All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. Kv currents were attributed to Kv7 channel activity based on their voltage dependence of activation (V0.5∼−34 mV), lack of inactivation, enhancement by flupirtine (a selective Kv7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective Kv7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced Kv7 currents but also inhibited voltage-sensitive Ca2+ currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca2+ channel blocker.
CONCLUSIONS AND IMPLICATIONS Kv7 channels are important determinants of basilar artery contractile status. Targeting the Kv7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm.
LINKED ARTICLES To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x