The Novel Dihydronaphthyridine Ca 2+ Channel Blocker CI-951 Improves CBF,Brain pH i,and EEG Recovery in Focal Cerebral Ischemia

Abstract

The effects of the novel dihydronaphthyridine Ca²⁺ antagonist CI-951 on focal cerebral ischemia were assessed during MCA occlusion in 30 white New Zealand rabbits under 1.0% halothane anesthesia. In vivo brain pH_i and focal CBF were measured with umbelliferone fluorescense. Baseline normocapnic brain pH_i and CBF were 7.02 ± 0.02 and 48.4 ± 2.9 ml/100 g/min, respectively. In the severe ischemic regions, 15 min postocclusion brain pH_i, and CBF were 6.62 ± 0.04 and 14.4 ± 0.7 ml/100 g/min in controls vs. 6.60 ± 0.02 and 12.9 ± 2.3 ml/100 g/min, respectively, in animals destined to receive CI-951. Twenty minutes after MCA occlusion, CI-951 was administered at 0.5 μg/kg/min and brain pH_i and CBF were determined in both regions of severe and moderate ischemia for 4 h postocclusion. Control severe ischemic sites demonstrated no significant improvement in brain pH_i and only mild increases in CBF over the next 4 h. CI-951 caused significant improvement in both of these parameters. Postocclusion 4 h brain pH_i and CBF measured 6.69 ± 0.04 and 18.5 ± 3.2 ml/100 g/min in controls vs. 7.01 ± 0.04 and 41.7 ± 5.3 ml/100 g/min, respectively, in CI-951 animals (p < 0.001). Similar improvements were observed in moderate ischemic sites. In animals that demonstrated postocclusion EEG attenuation, 75% of CI-951 animals had EEG recovery as compared to 18% in controls. CI-951 may be a useful therapeutic agent for focal cerebral ischemia if histological and outcome studies verify these data.