Preclinical efficacy and safety of Kv7 potassium channel openers in the treatment of cerebral vasospasm

Cerebral vasospasm is a sequel to subarachnoid hemorrhage (SAH) that leads to death or disability due to cerebral ischemia. The persistent constriction of the conduit arteries in the brain is due to sustained depolarization of myocytes lining the arteries, resulting in continuous influx of calcium (Ca 2+ ) through voltage‐gated Ca 2+ channels. Ca 2+ channel blockers (CCB) or potassium (K + ) channel openers that oppose membrane depolarization are expected to dilate the arteries and reduce ischemia. CCBs have limited efficacy because of heterogenous expression of Ca 2+ channel subunits in myocytes and their propensity to induce hypotension. We recently reported that Kv7channels are expressed in rat basilar artery myocytes and Kv7 channel openers reverse the constriction of rat basilar artery produced by spasmogens — endothelin, serotonin and vasopressin. Here we demonstrate that Kv7 channel activators, retigabine and celecoxib significantly attenuate basilar artery spasm in a rat SAH model, when administered intraperitoneally every 12 hours for 48 hours. Both Kv7 channel openers induced hypothermia, an effect expected to limit neuronal damage. They also induced a transient drop in blood pressure (BP) generally lasting 30–60 min after each administration, but mean 24‐h BP measured using radio‐telemetry in normal rats was not changed. These results indicate that Kv7 channel openers can attenuate vasospasm without sustained hypotension.