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

Abstract

Mexiletine is a class Ib drug that is widely used to treat ventricular arrhythmias. This compound is mainly known as a sodium channel blocker, but studies 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-1 (ET-1), or 100-microM lysophosphatidic acid (LPA) in the presence or absence of 400-mM mexiletine. Vasoconstriction caused by KCl, ET-1, and LPA was inhibited by mexiletine. 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 exposed basilar arteries exhibited a spastic constriction that was partially reversed by topical application of 400-microM mexiletine. In a third set of experiments, 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 vasospasm. In a separate group of animals, 80- and 20-mg/kg/day t.i.d. of mexiletine was administered 21 hours post-SAH induction, to study the reversal of vasoconstriction. Microscopic analysis of vessels from controls (no SAH), SAH-only, and SAH + mexiletine groups indicated there was 71.43% vascular constriction in the SAH-only group compared with controls. Considerable vasorelaxation was seen in the prevention study, in which average arterial cross-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 < 0.001). Compared with controls, average arterial cross-sectional areas were reduced by 53.58% and 64.29% in the mexiletine 80- and 20-mg/kg/day reversal groups, respectively. Our findings indicate that mexiletine induces potent relaxation in cerebrovascular arteries contracted with various agents, and that it prevents and partially reverses SAH-induced vasoconstriction.