In vivo Binding of Nimodipine in the Brain: I. The Effect of Focal Cerebral Ischemia

Abstract

We report the regional variation in [3H]nimodipine binding in vivo during focal cerebral ischemia. After intravenous injection, 30 min of circulation of [3H]nimodipine was sufficient to establish a secular equilibrium of distribution in the brain. Rats sustained left middle cerebral and common carotid artery occlusions for 5 min, and 4, 24, and 48 h (n ≥ 6 per group). They were decapitated 30 min after injection of 250 μCi of [3H]nimodipine and their brains were submitted to autoradiography. The concentrations of [3H]nimodipine in plasma and brain structures, corrected for metabolism of nimodipine, were used to calculate the regional volumes of distribution ( V) in the ischemic left (L) and control right (R) hemispheres. Log (VL/VR) was then defined as the group mean of the logarithms of the left-to-right ratio of V of [3H]nimodipine. In the lateral caudate, binding of [3H]nimodipine on the ischemic side was highest within 5 min of occlusion. Log ( VL/ VR) in this region for the combined sham-operated and normal control rats and those after 5 min and 4 and 24 h of ischemia were −0.014 ± 0.025, 0.137 ± 0.056*, −0.201 ± 0.367, and −0.049 ± 0.370 (mean ± SD, *represents p < 0.01 compared with controls). By contrast, in the superior frontal cortex, values for log ( VL/ VR) in the same sequence were −0.016 ± 0.025, 0.028 ± 0.056, 0.284 ± 0.228*, and 0.224 ± 0.069*, thus showing a significant rise in [3H]nimodipine binding only at 4 h. Structures such as the cingulate and striate cortex, sufficiently removed from the ischemic core, showed only small changes in log ( VL/ VR) at all times. Correlating these data with CBF and histologic determinations performed in separate groups of rats, we conclude that [3H]nimodipine binding increases earlier in the more severely ischemic structures than in those with more moderate reductions in perfusion. Furthermore, when binding declines in a region where it was previously increased, infarction is likely. These studies afford new insight into the concept of ischemic penumbra and suggest that this model may allow testing for therapeutic effectiveness.