Systemic administration of mexiletine for attenuation of cerebral vasospasm following experimental subarachnoid haemorrhage

Mexiletine is a class Ib drug that is widely used to treat ventricular arrh ythmias. This compound is mainly known as a sodium channel blocker, but stu dies have demonstrated that it can also activate ATP-sensitive K+ channels and block Ca2+ channels. Recent in vitro data from experiments on liposomes indicate that mexiletine is also a potent antioxidant. The unique activity profile of this drug raised the possibility that it might be of benefit in limiting cerebral vasospasm. Our first series of experiments assessed the effects of mexiletine on transclivally exposed rabbit basilar arteries. The arteries were treated with 50-mM KCl, 20-nM endothelin-l (ET-I), or 100-mu M lysophosphatidic acid (LPA) in the presence or absence of 400-mM mexilet ine. Vasoconstriction caused by KCl, ET-1, and LPA was inhibited by mexilet ine. In a second series of experiments, subarachnoid haemorrhage (SAH) was induced in rabbits by injecting 3-ml of autologous arterial blood into the cisterna magna. Forty-eight hours after SAH induction, transclivally expose d basilar arteries exhibited a spastic constriction that was partially reve rsed by topical application of 400-mu M mexiletine. In a third set of exper iments, mexiletine was administered orally at dosages of 80-, 20, and 5-mg/ kg/day t.i.d., beginning 3 hours before SAH to study the prevention of vaso spasm. In a separate group of animals, 80- and 20mg/kg/day t.i.d. of mexile tine was administered 21 hours post-SAM induction, to study the reversal of vasoconstriction. Microscopic analysis of vessels from controls (no SAH), SAM-only, and SAM + mexiletine groups indicated there was 71.43% vascular c onstriction in the SAM-only group compared with controls. Considerable vaso relaxation was seen in the prevention study, in which average arterial cros s-sectional areas were reduced by only 17.86% and 39.29% in the mexiletine 80- and 20-mg/kg/day groups, respectively, compared with controls (p < 0.00 1). Compared with controls, average arterial cross-sectional areas were red uced by 53.58% and 64.29% in the mexiletine 80- and 20-mg/kg/day reversal g roups, respectively. Our findings indicate that mexiletine induces potent r elaxation in cerebrovascular arteries contracted with various agents, and t hat it prevents and partially reverses SAM-induced vasoconstriction.