Ultrastructural changes in the blood-brain barrier in rats after treatment with nimodipine and flunarizine. A comparison.

The idea of using induced hypertension to treat the symptomatic ischaemia resulting from vasospasm after subarachnoidal hemorrhage, and the effect of this therapy on the blood-brain barrier, is checked in animal experiments. This therapy is combined with the application of nimodipine, which is recognised as the standard medication for prophylaxis of vasospasm. The effects of the induced hypertension combination with Nimodipine and in combination with another calcium antagonist, Flunarizine are compared. Seventy-four narcotised rats, one group with 22 animals treated with Nimodipine and 22 with placebo, and a second group 20 animals treated with Flunarizine and 10 with placebo, are evaluated. The blood pressure is raised to 150-180 mmHg by i.v. application of norfenephrine and measured continuously. The standard tracer, horseradish peroxidase, is applied as indicator for the blood-brain barrier function. 15 minutes later the experimental animals are exsanguinated by perfusion with saline, then perfused with Karnovsky's solution. After removal, the brains are stained for peroxidase to visualise extravasation of the horseradish peroxidase, and after evaluation of the results each brain is assigned to its experimental group. In the Nimodipine group, a significant accumulation (p < 0.001) of perivascular deposits of peroxidase reaction product were found, these were not found in the placebo group. The Flunarizine group does not differ from its placebo group in the number of extravasates, and thus, with respect to protein extravasation, appears better than the Nimodipine group. In electron micrographs of the extravasates one sees intact tight junctions and a neuroendothelial transport, and also vesicles, filled with horseradish peroxidase in the endothelium, the muscle cells, and the brain parenchyma, which arise from pinocytosis. The vesicles, which transport the high-molecular-weight protein, horseradish peroxidase, also transport other proteins and can, therefore, cause a brain edema. It follows from these morphological results that Nimodipine can disrupt the blood brain barrier function and can, therefore, also interfere with cerebral autoregulation, which depends on the resistance of vessels.