The Blood-Brain Barrier in Acute and Chronic Hypertension

  • B. B. Johansson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 131)


Acute arterial hypertension, induced by vasoactive substances or by compression of the thoracic aorta, can increase the permeability of the blood-brain barrier (BBB) in experimental animals (1). The present review deals predominantly with the BBB to macromolecules, since that is the BBB function most commonly studied in experimental hypertension. The abnormal permeability associated with hypertension has a typical, patchy appearance, although the pattern varies somewhat with different experimental models (see below and 1–6). This BBB dysfunction, which is rapidly reversible when the pressure returns to normal levels (7), is a direct consequence of the increased mechanical stress on the endothelial cells caused by the high intravascular pressure (1). An early hypothesis stating that the increased permeability was due to ischemia has been refuted for the following reasons: 1) the increased permeability to macromolecules is evident within seconds after the pressure increase, while it takes much longer for ischemia to cause this change in the BBB (1); 2) the cerebral blood flow is higher in areas with disturbed permeability than in surrounding tissue (8,9); and 3) energy metabolism in the brain is not disturbed in shortlasting acute hypertension (10,11).


Cerebral Blood Flow Brain Edema Chronic Hypertension Hypertensive Encephalopathy Renal Hypertension 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Johansson, BB: Brain barrier pathology in acute arterial hypertension. In, Levi, G, Battistin, L, Lajtha, A (eds): Transport Phenomena in the Nervous System, New York, Plenum Press, 1976, pp 517–527.Google Scholar
  2. 2.
    Carlsson, C, Johansson, BB: Blood-brain barrier dysfunction after amphetamine administration in rats. Acta Neuropath 45: 125, 1978.CrossRefGoogle Scholar
  3. 3.
    Hedley-Whyte, ET, Lorenzo, AV, Hsu, DW: Protein transport across cerebral vessels during metrazole-induced convulsions. Am J Physiol 233: C74–C85, 1977.PubMedGoogle Scholar
  4. 4.
    Johansson, BB: The cerebrovascular permeability to protein after bicuculline and amphetamine administration in spontaneously hypertensive rats. Acta Neurol Scand 56: 397–404, 1977.CrossRefPubMedGoogle Scholar
  5. 5.
    Johansson, BB, Martinsson, L: The blood-brain barrier in awake rats in acute hypertension induced by adrenaline, noradrenaline or angiotensin. Acta Neurol Scand 60: 193–197, 1979.CrossRefPubMedGoogle Scholar
  6. 6.
    Petito, CK, Schaefer, JA, Plum, F: The blood-brain barrier in experimental seizures. In, Pappius HM, Feindel W (eds): Dynamics of Brain Edema, New York, Springer-Verlag, 1976, pp 38–42.Google Scholar
  7. 7.
    Johansson, BB, Linder, L-E: Reversibility of the blood-brain barrier dysfunction induced by acute hypertension. Acta Neurol Scand 57: 345–348, 1978.CrossRefPubMedGoogle Scholar
  8. 8.
    Bill, A, Linder, J: Sympathetic control of cerebral blood flow in acute arterial hypertension. Acta Physiol Scand 20: 91–95, 1976.Google Scholar
  9. 9.
    Johansson, BB: Regional cerebral blood flow in acute experimental hypertension. Acta Neurol Scand 50: 366–372, 1974.CrossRefPubMedGoogle Scholar
  10. 10.
    Fujishima, M, Onoyama, K, Oniki, H, et al: Effects of acute hypertension on brain metabolism in normotensive, renovascular hypertensive and spontaneously hypertensive rats. Stroke 9: 349–353, 1978.CrossRefPubMedGoogle Scholar
  11. 11.
    Johansson, BB, Siesjö, BK: Brain energy metabolism in angiotensin- induced acute hypertension in rats. Acta Physiol Scand 100: 182–186, 1977.CrossRefPubMedGoogle Scholar
  12. 12.
    Haggendahl, E, Johansson, BB: Effect of increased intravascular pressure on the blood-brain barrier to protein in dogs. Acta Neurol Scand 48: 271–275, 1972.CrossRefGoogle Scholar
  13. 13.
    Hardebo, JE, Edvinsson, L, MacKenzie, ET, et al: Regional brain uptake of noradrenaline following mechanical or osmotic opening of the blood-brain barrier. Acta Physiol Scand 101: 342–350, 1977.CrossRefPubMedGoogle Scholar
  14. 14.
    Pannier, JL, Leusen, I: Cerebral blood flow in cats after an acute hypertensive insult with damage to the blood- brain barrier. Stroke 6: 188–198, 1975.CrossRefPubMedGoogle Scholar
  15. 15.
    Rapoport, SI: Opening of the blood-brain barrier by acute hypertension. Exp Neurol 52: 467–479, 1976.CrossRefPubMedGoogle Scholar
  16. 16.
    Byrom, FB: The pathogenesis of hypertensive encephalopathy and its relation to the malignant phase of hypertension: Experimental evidence from the hypertensive rat. Lancet 2: 201–211, 1964.Google Scholar
  17. 17.
    Meyer, JS, Waltz, AG, Gotoh, F: Pathogenesis of cerebral vasospasm in hypertensive encephalopathy. II. The nature of increased irritability of smooth muscle of piai arterioles in renal hypertension. Neurology 10: 859–867, 1960.CrossRefGoogle Scholar
  18. 18.
    Auer, L: The sausage-string phenomenon in acutely induced hypertension - Arguments against vasospasm theory in the pathogenesis of acute hypertensive encephalopathy. Europ Neurol 17: 166–173, 1978.CrossRefPubMedGoogle Scholar
  19. 19.
    MacKenzie, ET, Strandgaard, S, Graham, DI, et al: Effects of acutely induced hypertension in cats on piai arteriolar caliber, local cerebral blood flow and the blood- brain barrier. Circ Res 39: 33–41, 1976.CrossRefPubMedGoogle Scholar
  20. 20.
    Johansson, BB, Linder, L-E: Cerebrovascular permeability to protein in the rat during nitrous oxide anaesthesia at various blood pressure levels. Acta Anaesth Scand 22: 463–466, 1978.CrossRefPubMedGoogle Scholar
  21. 21.
    Johansson, BB: Some factors influencing the damaging effect of acute arterial hypertension on cerebral vessels in rats. Clin Sci Mol Med 51: 41s–43s, 1976.Google Scholar
  22. 22.
    Johansson, B, Nilsson, B: The pathophysiology of the blood-brain barrier dysfunction induced by severe hypercapnia and by epileptic brain activity. Acta Neuropath 38: 153–158, 1977.CrossRefPubMedGoogle Scholar
  23. 23.
    Bolwig, TG, Hertz, MM, Westergaard, E: Acute hypertension causing blood-brain barrier breakdown during epileptic seizures. Acta Neurol Scand 56: 335–342, 1977.CrossRefPubMedGoogle Scholar
  24. 24.
    Johansson, BB: Effect of $-adrenoreceptor antagonists on the increased cerebrovascular permeability to protein induced by amphetamine. Prog Neuro Psychopharmac 2: 529–534, 1978.CrossRefGoogle Scholar
  25. 25.
    Edvinsson, L, MacKenzie ET: Amine mechanisms in the cerebral circulation. Pharmacol Rev 28: 275–348, 1976.PubMedGoogle Scholar
  26. 26.
    Nielsen, KC, Owman, C: Adrenergic innervation of pial arteries related to the circle of Willis in the cat. Brain Res 6: 773–776, 1967.CrossRefPubMedGoogle Scholar
  27. 27.
    Heistad, DD, Marcus, ML: Effect of sympathetic stimulation on permeability of the blood-brain barrier to albumin during acute hypertension in cats. Circ Res, In press.Google Scholar
  28. 28.
    MacKenzie, ET, McGeorge, AP, Graham, DI, et al: Breakthrough of cerebral autoregulation and the sympathetic nervous system. Acta Neurol Scand (Suppl 64) 56: 48–49, 1977.Google Scholar
  29. 29.
    Johansson, BB, Lund, S: Effect of sympathetic stimulation on the blood-brain barrier dysfunction induced by amphetamine and by epileptic seizures. Acta Physiql Scand 104: 281–286, 1978.CrossRefGoogle Scholar
  30. 30.
    Edvinsson, L, Hardebo, JE, Owman, C: Influence of the cerebrovascular sympathetic innervation on regional flow, auto-regulation, and blood-brain barrier function. In, Owman C and Edvinsson L (eds): Neurogenic Control of the Brain Circulation, Oxford, Pergamon Press, 1977, pp 387–401.Google Scholar
  31. 31.
    Johansson, BB: Neonatal sympathectomy increases the vulnerability of the blood-brain barrier to acute hypertension in conscious rats. Acta Neurol Scand 60: 198–203, 1979.CrossRefPubMedGoogle Scholar
  32. 32.
    Hartman, BK, Zide, D, Udenfriend, S: The use of dopamine hydroxylase as a marker for the central nervous system in rat brain. Proc Natl Acad Sci 66: 2722–2726, 1972.CrossRefGoogle Scholar
  33. 33.
    Rennels, M, Nelson, E: Capillary innervation in the mammalial central nervous system. An electron microscopic demonstration. Am J Anat 144: 233–241, 1975.CrossRefPubMedGoogle Scholar
  34. 34.
    Bates, D, Weinshilboum, RM, Campbell, RJ, et al: The effect of lesions in the locus coeruleus on the physiological responses of the cerebral vessels in cats. Brain Res 136: 431–433, 1977.CrossRefPubMedGoogle Scholar
  35. 35.
    Raichle, ME, Hartman, BK, Eichling, JO, et al: Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Natl Acad Sci 72: 3726–3730, 1975.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Grubb, RL Jr, Raichle, ME, Eichling, JO: Peripheral sympathetic regulation of brain water permeability. Acta Neurol Scand (Suppl 64) 56: 490–491, 1977.Google Scholar
  37. 37.
    Eisenberg, HM, Barlow, CF, Lorenzo, AV: Effect of dexamethasone on altered brain vascular permeability. Arch Neurol 23: 18–22, 1970.CrossRefPubMedGoogle Scholar
  38. 38.
    Johansson, BB: Effect of dexamethasone on protein extravasation in the brain in acute hypertension induced by amphetamine. Acta Neurol Scand 57: 180–185, 1978.CrossRefPubMedGoogle Scholar
  39. 39.
    Hansson, H-A, Johansson, BB: Prevention of protein extravasation in the brain by an anion transport inhibitor in acute experimental hypertension in rats. Acta Physiol Scand 105: 513–517, 1979.CrossRefPubMedGoogle Scholar
  40. 40.
    Larsson, B, Skärby, T, Edvinsson, L, et al: Evidence for involvement of microtubules in the enhanced transendothelial pinocytosis in the blood-brain barrier induced by high intravascular pressure. Acta Neurol Scand (Suppl 72) 60: 80–81, 1979.Google Scholar
  41. 41.
    Johansson, BB, Linder, L-E, Persson, L: Blood-brain barrier in hypertension in awake and N20-anesthetized rats. Acta Neurol Scand (Suppl 72) 60: 42–43, 1979.Google Scholar
  42. 42.
    Forster, A, van Horn, K, Marshall, LF, et al: Influence of anesthetic agents on blood-brain barrier function during acute hypertension. Acta Neurol Scand (Suppl 64) 56: 60–61, 1977.Google Scholar
  43. 43.
    Johansson, BB: Effect of an acute increase of the intravascular pressure on the blood-brain barrier. A comparison between conscious and anesthetized rats. Stroke 9: 588–590, 1978.CrossRefPubMedGoogle Scholar
  44. 44.
    Strandgaard, S: Autoregulation of cerebral circulation in hypertension. Acta Neurol Scand (Suppl 66, 57: 1–82, 1978.Google Scholar
  45. 45.
    Gannushkina, IV, Shafranova, VP: Morphological and pathophysiological background of brain tissue spotty damage due to acute hypertension. In, Mossakowski MJ, Zelman IB, Krogh H (eds): Pathophysiological, Biochemical and Morphological Aspects of Cerebral Ischemia and Arterial Hypertension, Warsaw, Polish Medical Publishers, 1978, pp 163–170.Google Scholar
  46. 46.
    Johansson, BB, Nilsson, B: Cerebral vasomotor reactivity in normotensive and spontaneously hypertensive rats. Stroke 10: 572–576, 1979.CrossRefPubMedGoogle Scholar
  47. 47.
    Ekstrom-Jodal, BE, Haggendal, E, Johansson, B, et al: Acute arterial hypertension and the blood-brain barrier. An experimental study in dogs. In, Langfitt TW, McHenry LC Jr, Reivich M, Wollman H (eds): Cerebral Circulation and Metabolism. New York, Springer-Verlag, 1975, pp 7–9.Google Scholar
  48. 48.
    Auer, LM: The pathogenesis of hypertensive encephalopathy. Acta Neurochir Suppl 27, 1978.Google Scholar
  49. 49.
    Reese, TS, Karnovsky, MJ: Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34: 207–217, 1967.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hansson, H-A, Johansson, BB, Blomstrand, C: Ultrastructural studies on cerebrovascular permeability in acute hypertension. Acta Neuropath 32: 187–198, 1975.CrossRefPubMedGoogle Scholar
  51. 51.
    Kung, PC, Lee, JC, Bakay, L: Electron microscopic study of experimental acute hypertensive encephalopathy. Acta Neuropath 10: 263–272, 1968.CrossRefPubMedGoogle Scholar
  52. 52.
    Lorenzo, AV, Hedley-Whyte, ET, Eisenberg, HM, et al: Increased penetration of horseradish peroxidase across the blood- brain barrier induced by Metrazol seizures. Brain Res 88: 136–140, 1975.CrossRefPubMedGoogle Scholar
  53. 53.
    Nag, S, Robertson, DM, Dinsdale, HB: Cerebral cortical changes in acute experimental hypertension. An ultrastructural study. Lab Invest 36: 150–161, 1977.PubMedGoogle Scholar
  54. 54.
    Petito, CK, Schaefer, JA, Plum, F: Ultrastructural characteristics of the brain and blood-brain barrier in experimental seizures. Brain Res 127: 251–267, 1977.CrossRefPubMedGoogle Scholar
  55. 55.
    Westergaard, E, van Deurs, B, Brønsted, HE: Increased vesicular transfer of horseradish peroxidase across cerebral endothelium, evoked by acute hypertension. Acta Neuro-path. 37: 141–152, 1977.CrossRefGoogle Scholar
  56. 56.
    Johansson, BR: Perbeability of muscle capillaries to interstitially microinjected horseradish peroxidase. Microvasc Res 16: 340–353, 1978.CrossRefPubMedGoogle Scholar
  57. 57.
    Giacomelli, F, Rooney, J, Wiener, J: Cerebrovascular ultra-structure and permeability after carotid artery constriction in experimental hypertension. Exp Molec Path 28: 309–321, 1978.CrossRefPubMedGoogle Scholar
  58. 58.
    Johansson, B, Henning, M: Clinical effect of acute blood pressure increase in conscious rats. Acta Physiol Scand 98: 376–378, 1976.CrossRefPubMedGoogle Scholar
  59. 59.
    Giacomelli, F, Wiener, J, Spiro, D: The cellular pathology of experimental hypertension. V. Increased permeability of cerebral arterial vessels. Am J Path 59: 133–159, 1970.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Okamoto, K, Aoki, K: Development of a strain of spontaneously hypertensive rats. Jap Circulat J 27: 282–293, 1963.CrossRefGoogle Scholar
  61. 61.
    Okamoto, K. Yamori, Y, Nagaoka, A: Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circulat Res (Suppl 1) 34: 143–153, 1974.CrossRefGoogle Scholar
  62. 62.
    Johansson, BB, Nordborg, C: Cerebral vessels in spontaneously hypertensive rats. In, Cervds-Navarro C, Betz E, Ebhardt G, Ferszt R, Wullenweber R (eds): Pathology of Cerebrospinal Microcirculation, New York, Raven Press, 1978, pp 349–357.Google Scholar
  63. 63.
    Cook, TA, Yates, PO: A histometric study of cerebral and renal arteries in normotensive and chronic hypertensives. J Path 108: 129–135, 1972.CrossRefPubMedGoogle Scholar
  64. 64.
    Ross Russel, RW: Observations on intracerebral aneurysms. Brain 86: 425–442, 1963.CrossRefGoogle Scholar
  65. 65.
    Fujishima, M, Ogata, J, Sugi, T, et al: Mortality and cerebral metabolism after bilateral carotid artery ligation in normotensive and spontaneously hypertensive rats. J Neurol Neurosurg Psych 39: 212–217, 1976.CrossRefGoogle Scholar
  66. 66.
    Yamori, Y, Horie, R, Sato, M, et al: Experimental studies on the pathogenesis and prophylaxis of stroke-prone spontaneously hypertensive rats (SHR) (1) Quantitative estimation of cerebrovascular permeability. Jap Circ J 39: 611–615, 1975.CrossRefPubMedGoogle Scholar
  67. 67.
    Hazama, F, Amano, S, Haebara, H, et al: Changes in vascular permeability in the brain of stroke-prone spontaneously hypertensive rats studied with peroxidase as a tracer. Acta Path Jap 25: 565–574, 1975.PubMedGoogle Scholar
  68. 68.
    Hazama, F, Ozaki, T, Amano, S: Scanning electron microscopic study of endothelial cells of cerebral arteries from spontaneously hypertensive rats. Stroke 10: 245–252, 1979.CrossRefPubMedGoogle Scholar
  69. 69.
    Shibota, M, Shino, A, Nagaoka, A: Cerebrovascular permeability in stroke-prone spontaneously hypertensive rats. Exp Molec Path 28: 330–337, 1978.CrossRefPubMedGoogle Scholar
  70. 70.
    Yamori, Y, Horie, R: Developmental course of hypertension and regional cerebral blood flow in stroke-prone spontaneously hypertensive rats. Stroke 8: 456–461, 1977.CrossRefPubMedGoogle Scholar
  71. 71.
    Klatzo, I: Neuropathological aspects of brain edema: Presidential Address. J Neuropath Exp Neurol 26: 1–14, 1967.CrossRefPubMedGoogle Scholar
  72. 72.
    Klatzo, I, Wisniewski, H, Steinwall, O, et al: Dynamics of cold injury edema. In, Klatzo I and Seitelberger F (eds): Brain Edema, New York, Springer-Verlag, 1967, pp 554–563.CrossRefGoogle Scholar
  73. 73.
    Schutta, HS, Kassel, NF, Langfitt, TW: Brain swelling produced by injury and aggravated by arterial hypertension. Brain 91: 281–294, 1968.CrossRefPubMedGoogle Scholar
  74. 74.
    Johansson, BB: Water content of rat brain in acute arterial hypertension. In, Pappius HM, Fendel W (eds): Dynamic Aspects of Brain Edema, New York, Springer-Verlag, 1976, pp 28–31.Google Scholar
  75. 75.
    Meinig, G, Reulen, HJ, Simon, CH, et al: Cerebrale vasoparalyse, arterielle hypertension and hirnodem. J Neurol 211: 25–38, 1975.CrossRefPubMedGoogle Scholar
  76. 76.
    Nelson, SR, Mantz, M-L, Maxwell, JA: Use of specific gravity in the measurement of brain edema. J Appl Physiol 30: 268–271, 1971.PubMedGoogle Scholar
  77. 77.
    Byrom, FB: The Hypertensive Vascular Crisis. An Experimental Study, London, Heinemann, 1969.Google Scholar
  78. 78.
    Sellser, MI, Lavender JF: Studies on the interrelationship between the blood-brain barrier and entry of viruses into the central nervous system. J Exp Med 115: 107–129, 1962.CrossRefGoogle Scholar
  79. 79.
    Oldendorf, WH: Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection. Am J Physiol 221: 1629–1638, 1971.PubMedGoogle Scholar
  80. 80.
    Hardebo, JE, Edvinsson, L, MacKenzie, ET, et al: Histofluorescence study on monoamine entry into the brain before and after opening of the blood-brain barrier by various mechanisms. Acta Neuropath 47: 145–150, 1979.CrossRefPubMedGoogle Scholar
  81. 81.
    Abdul-Rahman, A, Dahlgren, N, Johansson, BB: Increase in local cerebral blood flow induced by circulating adrenaline: Involvement of blood-brain barrier dysfunction. Acta Physiol Scand, In press.Google Scholar
  82. 82.
    MacKenzie, ET, McCulloch, J, O’Keane, M, et al: Cerebral circulation and norepinephrine: Relevance of the blood- brain barrier. Am J Physiol 231: 483–488, 1976.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • B. B. Johansson
    • 1
  1. 1.Department of NeurologyUniversity of Göteborg Sahlgren HospitalGöteborgSweden

Personalised recommendations