Pharmacological influences on cardiopulmonary arrest-related brain damage in the rat

The aim of the present work was to evaluate the protective properties of the calcium-entry blocker nimodipine against brain damage induced by cardiopulmonary arrest in a rat model. We studied first the effect of nimodipine administered in a blind and randomized fashion and started 5 min after the restoration of spontaneous circulation. Our experiments showed no improvement of survival, and nimodipine did not improve the neurological outcome in the animals surviving after 7 days. We even observed a trend toward a decreased survival rate when higher doses of nimodipine were used. In order to evaluate whether the lack of protective effect of nimodipine might have been due to the fact that it was given too late, we administered nimodipine in the second series of experiments at the earliest feasible postischemic moment, i.e. at the start of the resuscitation attempts. However, this study also failed to show an improved outcome in nimodipine-treated animals; there was even a significantly decreased resuscitation rate. In order to exclude that a cerebroprotective effect was antagonized by deleterious effects of nimodipine on the cardiovascular system, which may be especially vulnerable after resuscitation, we also studied nimodipine in the 4-vessel occlusion model in the rat. Indeed, in contrast to the cardiopulmonary arrest model, cardiovascular depression does not occur in this model. In these experiments, we started the administration of nimodipine before the induction of global brain ischemia, used 2 different dosage regimens and provided prolonged drug administration after restoration of cerebral blood flow in order to create optimal circumstances for a cerebroprotective effect to be detected. These experiments, however, also failed to show any cerebroprotective effect of nimodipine. In this 4-vessel occlusion model, we also evaluated, as a control drug, 1,3-butanediol, an alternate substrate for brain metabolism during ischemia that has been shown to offer cerebral protection in this animal model. Our results could, however, not confirm this beneficial effect. We conclude that in the rat there is no cerebroprotective effect of the calcium-entry blocker nimodipine on global brain ischemia as present during cardiopulmonary arrest. On the contrary, we even observed adverse effects, especially when high doses are used and/or when the drug is given during resuscitation attempts.