MR evaluation of calcium entry blockers with putative cerebroprotective effects in acute cerebral ischaemia

MR imaging and spectroscopy were used to investigate whether two calcium channel entry-blockers, nicardipine and RS-87476 (Syntex), would reduce ischaemic brain damage in barbiturate-anaesthetized cats subjected to permanent unilateral occlusion of the middle cerebral artery (MCA). The evolution of cerebral injury was assessed in vivo in a total of 38 cats using a combination of diffusion-weighted and T2-weighted spin-echo proton MR imaging and phosphorus 31 (P-31) and proton (H-1) MR spectroscopy for up to 12 h following arterial occlusion. Immediately thereafter, the volume of histochemically ischaemic brain tissue was determined planimetrically. In untreated control animals, diffusion-weighted MR images obtained with strong gradient strengths (5.5 gauss/cm) displayed increased signal intensity (oedema) in the ischaemic MCA territory less than 45 min after stroke. These changes were closely correlated with the appearance of abnormal P-31 and H-1 metabolite levels evaluated with surface coil MR spectroscopy. Cats injected with i.v. nicardipine (10 micrograms/kg bolus, 8 micrograms/kg/h maintenance) or RS-87476 (2-50 micrograms/kg bolus, 0.7-17.5 micrograms/kg/h maintenance) showed a significant reduction in ischaemic injury in the ipsilateral cerebral cortex, internal capsule and basal ganglia. The results of this study suggest that these calcium entry blockers protect against brain damage induced by acute stroke by stabilizing cellular metabolic processes, reducing lactate formation in ischaemic tissues, and attenuating cytotoxic and vasogenic oedema.