Cerebral Blood Flow and Neurologic Outcome When Nimodipine is Given after Complete Cerebral Ischemia in the Dog

Abstract

Ten minutes of complete cerebral ischemia was produced in 26 dogs by temporary ligation of the aorta and the venae cavae. Twenty dogs received nimodipine, a calcium entry blocker, 10 micrograms kg-1 i.v. 2 min after the ischemic period, followed by 1 microgram kg-1 min-1 for 2-3 h. Six dogs received only the solvent used for nimodipine. Fourteen dogs received nimodipine for 3 h and were subsequently evaluated neurologically up to 48 h postischemia. In the 12 other dogs, CBF and metabolism were followed for 2 h postischemia while either nimodipine or the solvent only was infused. The results were compared to previously published results for untreated dogs and dogs given nimodipine before the ischemic event. Nimodipine had the same effect on postischemic CBF whether started before or after the ischemic event, nearly doubling the flow when compared with untreated controls, whereas the solvent alone caused only a slight increase in CBF over control. By contrast, nimodipine initiated in the preischemic period significantly improved the neurologic outcome, but when initiated in the postischemic period the results were equivocal, such that the outcome was not significantly different from either the untreated group or the group in which nimodipine was initiated preischemia. Metabolic measurements did not give any indication of a specific effect of nimodipine, nor could the metabolic results be used as an indicator of neurologic outcome. The results are consistent with a beneficial effect of nimodipine following complete cerebral ischemia; however, evaluation of neurologic functional effects will require a more sensitive model.

The effect of the calcium antagonist nimodipine on the gerbil model of experimental cerebral ischemia.

“…" 16 A consistent finding in previous experiments and in ours has been that treatment with nimodipine improves survival after ischemic cerebral damage. In order to understand how nimodipine may benefit the gerbils with predicted 100% mortality, we should know the pathophysiological cause of death.…”

Failure of flunarizine to improve cerebral blood flow or neurologic recovery in a canine model of complete cerebral ischemia.

“…9 Since the only measured variable that was improved by nimodipine was CBF, it was concluded that the post-ischemic hypoperfusion state does appear to contribute to the ultimate neurologic damage. In an identical study except that nimodipine was given only after the ischemic event, CBF was again higher during the hypoperfusion period in the nimodipine group 10 (CBF = 51 miyiOOg-'/min-', 34% of pre-ischemic control) than the untreated group. 4 However, in the neurologic function studies, when nimodipine was given only after ischemia, 10 neurologic outcome was intermediate and not significantly different from either the untreated group 14 or the pre-treated nimodipine group.'…”

“…In an identical study except that nimodipine was given only after the ischemic event, CBF was again higher during the hypoperfusion period in the nimodipine group 10 (CBF = 51 miyiOOg-'/min-', 34% of pre-ischemic control) than the untreated group. 4 However, in the neurologic function studies, when nimodipine was given only after ischemia, 10 neurologic outcome was intermediate and not significantly different from either the untreated group 14 or the pre-treated nimodipine group.' Flunarizine has been reported to be a potent inhibitor of calcium-induced constriction of isolated arteries, 24 being most effective in cerebral arteries.…”

“…7 Accordingly, an effective cerebral vasodilator might have a significant impact upon the neurologic outcome follow-ing a period of complete cerebral ischemia. Nimodipine, a calcium entry blocker, has been reported to inhibit vasoconstriction in potassium depolarized vascular smooth muscle; 8 to moderately improve cerebral blood flow (CBF) following a period of complete global ischemia in dogs 9 " 10 and to improve neurologic outcome. 9 Another calcium entry blocker, flunarizine, has been reported to be a potent cerebral vasodilator," to dramatically improve CBF after complete cerebral ischemia in dogs maintained on cardiopulmonary bypass, 12 and to protect the brain of mice and rats against cerebral hypoxia-anoxia.…”

A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia.

“…However, selective antagonists of excitatory amino acid receptors-in particular, N-methyl-D-aspartate (NMDA) antagonists-have not been effective in protecting the vulnerable CAl neurons in the four-vessel occlusion model of transient forebrain ischemia in rats (5-7). Similarly, classical calcium channel antagonists such as the dihydropyridines, which block L-type calcium channels, have also failed to protect neurons from the consequences of ischemia when administered after the ischemic episode (8,9). To develop therapies for preventing the brain damage caused by ischemia, we have investigated the utility of selectively blocking N-type calcium channels.…”