Pretreatment of transient focal cerebral ischemia in rats with the calcium antagonist AT877.

Abstract

The efficacy of pretreatment with the recently developed intracellular calcium antagonist AT877 against transient focal cerebral ischemia was investigated in rats subjected to middle cerebral artery occlusion and reperfusion using the endovascular suture method. Halothane-induced moderate hypotension (60 mm Hg) was used during 100 minutes of temporary middle cerebral artery occlusion. In the treated animals (n = 10), an intravenous infusion of AT877 (0.03 mg/kg per minute) was initiated 30 minutes before the ischemic event and continued during the ischemic period. The control rats (n = 10) received physiological saline in a similar fashion. Local cerebral blood flow was measured by the hydrogen clearance technique. Neurological examinations were performed daily during the 48-hour observation period, and infarct size was assessed by triphenyltetrazolium chloride staining. A continuous infusion of AT877 significantly improved local cerebral blood flow during ischemia. The treated animals showed a better neurological outcome after a 24-hour observation period, and a significant reduction in ischemic brain injury resulted in both the neocortex (149 +/- 20 versus 41 +/- 14 mm3, P < .01) and the striatum (80 +/- 5 versus 46 +/- 8 mm3, P < .05). The size of the neocortical infarct was reduced, with increasing mean ischemic cerebral blood flow in the control and treated animals (r = .923, P = .0001). AT877 pretreatment was effective in preventing brain injury during transient focal cerebral ischemia and improving neurological status. This beneficial effect seems to be mediated, in part, by its primary action of increasing cerebral blood flow.