Abstract
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.
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References
Allen GS, HS Ahn, TJ Preziosi: Cerebral arterial spasm — a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308 (1968) 619–624
Auer LM: Acute surgery of cerebral aneurysms and prevention of symptomatic vasospasm. Acta Neurochir 69 (1983) 273–281
Awad IA, LP Carter, RF Spetzler, M Medina, FW Williams Jr: Clinical vasospasm after subarachnoid hemorrhage: Response to hypervolemic hemodilution and arterial hypertension. Stroke 18 (1987) 365–372
Broadwell RD: Transcytosis of macromolecules through the blood-brain-barrier: a cell biological perspective and critical appraisal. Acta Neuropath 79 (1989) 117–128
Brøndsted HE, E Westergaard: Increased vesicular transport of horseradish peroxidase across the bloodbrain barrier after chemical induction of hypertension. In: J Ceryos-Navarro (ed): Advances in Neurology. Vol. 20, Raven Press, New York, 1978
Desphanade JK, T Wieloch: Flunarizine, a calcium entry blocker, ameliorates ischemic brain damage in the rat. Anesthesiology 64 (1986) 215–224
Doczi T: The pathogenic and prognostic significance of blood-brain barrier damage at the acute stage of aneurysmal subarachnoid haemorrhage. Clinical and experimental studies. Acta Neurochir 77 (1985) 110–132
Durward QJ, RF Del Maestro, AL Amacher: The influence of systemic arterial pressure and intracranial pressure on the development of cerebral vasogenic edema. J Neurosurg 59 (1983) 803–809
Farrar JK, IV Jones, DI Graham, S Strandgaard, ET McKenzie: Evidence against cerebral vasospasm during acutely induced hypertension. Brain Res 104 (1976) 176–180
Finn SS, SA Stephensen, CA Miller: Observations of the perioperative management of aneurysmal subarachnoid hemorrhage. J Neurosurg 65 (1986) 48–62
Giacomelli F, J Wiener, D Spira: The cellular pathology experimental hypertension. Am J Pathol 59 (1979) 134–152
Gunn AJ, T Mydlar, L Bennet, RLM Faul, S Gorter, C Cook: The neuroprotective actions of a calcium channel antagonist, flunarizine, in the infant rat. Ped Res 25 (1989) 573–576
Hansson HA, B Johansson, C Blømstrand: Ultrastructural studies on cerebrovascular permeability in acute hypertension. Acta Neuropathol 32 (1975) 187–198
Hatashita S, JT Hoff, S Ishii: Focal brain edema associated with acute arterial hypertension. J Neurosurg 64 (1986) 643–649
Heistad DD, ML Marcus, PM Gross: Effects of sympathetic nerves on cerebral vessels in dog, cat and monkey. Am J Physiol 235 (1978) H544-H552
Heistad DD, HA Kontos: Cerebral Circulation. In: JT Shepherd, FM Abbourd (eds): Handbook of Physiology Section 2. The cardiovascular system. Bethesda Am Physiol Soc (1983) 137–182
Heistad DD. Protection of the blood-brain barrier during acute and chronic hypertension. Federat Proc 43 (1984) 205–209
Höllerhage HG, MR Gaab, M Zumkeller, GF Walter: The effect of nimodipine on cerebral blood flow autoregulation and blood-brain barrier. J Neurosurg 69 (1988) 919–922
Jagenau A, W Melis, J Van Loon, A Wauquier: Effects of i.v. flunarizine on experimentally induced cerebral vasospasm in dogs. Dept Appl Pharmacol Neuropharmacol, Janssen Pharmaceutica, B-2340, Belgium (1990)
Karnovsky MJ: The ultrastructural basis of capillary permeability studied with peroxydase as a tracer. J Cell Biol 35 (1967) 213–236
Karnovsky MJ, SM Shea: Transcapillary transport by pinocytosis. Microvasc Res 2 (1970) 353–360
Kassell NF, SJ Peerless, QJ Durward, DW Beck, CG Drake, HP Adams. Treatment of ischemic effects from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery 11 (1982) 337–343
Lossinsky MJ, JH Garcia, L Iwanowski, WL Lightfoote: New ultrastructural evidence for a protein transport system in endothelial cells of gerbill brains. Acta Neuropathologica 47 (1979) 105ff
Matthaei S, R Horuk, JM Olefasky: Blood-brain glucose transfer in diabetes mellitus. Decreased number of glucose transporters at blood-brain barrier. Diabetes 35 (1986) 1181–1186
Mayhan WG, FM Faraci, JL Siems, DD Heistad: Role of molecular charge in disruption of the blood-brain barrier during acute hypertension. Circ Res 64 (1989) 658–664
Muizelaar JP, DP Becker: Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow. Surg Neurol 25 (1986) 317–325
Nag S, DM Robertson, HB Dinsdale: Cerebral cortical changes in acute experimental hypertension. Labor Invest 36 (1977) 150–161
Nag S, DM Robertson, HB Dinsdale: Quantitative estimate of pinocytosis in experimental acute hypertension. Acta Neuropathol 46 (1979) 107–116
Nag S, DM Robertson, HB Dinsdale: Morphological changes in spontaneously hypertensive rats. Acta Neuropathol 52 (1980) 27–34
Nag S: Cerebral change in chronic hypertension: Combined permeability and immunohistochemical studies. Acta Neuropathol (Berlin) 62 (1984) 178–184
Nag S: Cerebral endothelial surface charge in hypertension. Acta Neuropathol 63 (1984) 276–281
Nag S, L Young: Cerebrovascular permeability in acute hypertension: Effect of flunarizine. Brain Edema 1990. The eighth international Symposium June 17–20 1990 Bern/Switzerland 142, 1990
Nag S: Protective effect of flunarizine on blood-brain barrier permeability alterations in acutely hypertensive rats. Stroke 22 (1991) 1265–1269
Noguchi Y, Y Shibata, T Yamammoto: Endothelial vesicular system in rapid frozen muscle capillaries revealed by serial sectioning and deep etching. Anat Rec 217 (1987) 355–360
Rapoport SI: Effect of concentrated solutions on blood-brain barrier. Am J Physiol 219 (1970) 270–274
Rapoport SI: Osmotic opening of the blood-brain barrier. Ann Neurol 24 (1988) 677–684
Reese TS, MJ Karnovsky: Fine structural localisation of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34 (1967) 209–217
Sokrab TEO, BB Johansson, H Kalimo, Y Olsson: A transient hypertensive opening of the blood-brain barrier can lead to brain damage. Acta Neuropathol (Berlin) 75 (1988) 557–565
Sonkodi S, F Joo, M Maurer: The permeability state of the blood-brain barrier in relation with the plasma renin activity in early stage of experimental renal hypertension. Br J Exp Path 51 (1970) 448–452
Vorbrodt AW, AS Lossinsky, AM Wiesniesky, R Suzuki, T Yamaguchi, I Klatzo: Ultrastructural observations on the transvascular route of protein removal in vasogenic brain edema. Acta Neuropathol (Berlin) 65 (1985) 265–273
Wauquier A: Calcium entry blockers in cardiovascular and cerebral dysfunctions. In: Th Godfraind, AG Hermann, D Wellen (eds). Calcium entry blockers. Martinus Nijhoff Publ Boston-The Hague-Dordrecht-Lancaster 1984
Werber AH, MPC Fitch-Burke: Effect of chronic hypertension on acute hypertensive disruption of the blood-brain barrier in rats. Hypertension 12 (1988) 549–555
Westergaard E, MW Brightman: Transport of protein across normal cerebral arterioles. J Comp Neurol 152 (1973) 17–44
Westergaard E, B van Deurs, HE Brøndsted: Increased vesicular transfer of horseradish peroxidase across cerebral endothelium, evoked by acute hypertension. Acta Neuropathol 37 (1977) 141–152
Wolman M, I Klatzo, E Chui, F Wilmes, K Nishimoto, K Fujiwara: Evaluation of the dye-protein tracers in pathophysiology of the blood-brain barrier. Acta Neuropathol 54 (1981) 55–61
Zumkeller M, HG Höllerhage, E Reale, H Dietz: Ultrastructural changes in the blood-brain barrier after nimodipine treatment and induced hypertension. Exper Neurol 113 (1991) 315–321
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Zumkeller, M., Dietz, H. Ultrastructural changes in the blood-brain barrier in rats after treatment with Nimodipine and Flunarizine. A comparison. Neurosurg. Rev. 19, 253–260 (1996). https://doi.org/10.1007/BF00314841
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DOI: https://doi.org/10.1007/BF00314841