Advertisement

Target Organ Modification in Pharmacology: Reversible Osmotic Opening of the Blood-Brain Barrier by Opening of Tight Junctions

  • Stanley I. Rapoport

Abstract

We often consider how to modify the physical-chemical properties of a drug—its distribution, excretion, and metabolism—so as to increase its effective action at the target organ. In this paper I shall discuss how a target organ itself—the brain and blood-brain barrier system—can be modified to facilitate entry of normally excluded drugs. I shall present physiological and morphological evidence that the blood-brain barrier can be opened osmotically in a reversible manner without producing gross neurological damage to the animal.

Keywords

Tight Junction Evans Blue Lipid Solubility Carbamate Ethyl Lingual Artery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Brightman, M. W., Hon, M., Rapoport, S. I., Reese, T. S., and Westergaard, E., 1973 “Osmotic opening of tight junctions in cerebral endothelium,’ J. Comp. Neurol. 152: 317–326.PubMedCrossRefGoogle Scholar
  2. Brightman, M. W., and Reese, T. S., 1969, “Junctions between intimately apposed cell membranes in the vertebrate brain,” J. Cell. Biol. 40: 648–677.PubMedCrossRefGoogle Scholar
  3. Broman, T., 1949, The Permeability of the Cerebrospinal Vessels in Normal and Pathological Conditions, Munksgaard, Copenhagen.Google Scholar
  4. Coceani, F., Libman, I., and Gloor, P., 1966, “The effect of intracarotid amobarbital injections upon experimentally induced epileptiform activity,” EEG Clin. Neurophysiol. 20: 542–558.CrossRefGoogle Scholar
  5. Collander, R., and Bärlund, H., 1933, “Permeabilitätsstudien an Chara Ceratophylla,” Acta Botan. Fenn 11: 1–20.Google Scholar
  6. Crone, C., 1965, “The permeability of brain capillaries to nonelectrolytes,” Acta Physiol. Scand. 64: 407–417.PubMedCrossRefGoogle Scholar
  7. Davson H., 1967, Physiology of the Cerebrospinal Fluid, J & A Churchill, London.Google Scholar
  8. Diamond, J. M., and Wright, E. M., 1969, “Biological membranes: The physical basis of ion and nonelectrolyte selectivity,” Ann. Rev. Physiol. 31: 581–646.CrossRefGoogle Scholar
  9. Fenstermacher, J. D., and Johnson, J. A., 1966, “Filtration and reflection coefficients of the rabbit blood-brain barrier,” Am. J. Physiol. 211: 341–346.PubMedGoogle Scholar
  10. Hartman, C. G., and Straus, W. L., 1933, The Anatomy of the Rhesus Monkey, Hafner, New York.Google Scholar
  11. Höber, R., 1945, Physical Chemistry of Cells and Tissues, Blakiston, Philadelphia.Google Scholar
  12. Karnovsky, M. J., 1968, “The ultrastructural basis of transcapillary exchanges,” J. Gen. Physiol. 52: 64s–95s.CrossRefGoogle Scholar
  13. Katchalsky, A., and Curran, P. F., 1965, Nonequilibrium Thermodymanics in Biophysics, Harvard University Press, Cambridge.Google Scholar
  14. Krogh, A., 1946, “The active and passive exchanges of inorganic ions through the surfaces of living cells and through living membranes generally,” Proc. Roy. Soc. Ser. B. 133: 140–200.CrossRefGoogle Scholar
  15. Kuwabara, T., 1970, Fine Structure of the Eye, 2nd ed., Harvard Univ. Med. School, Boston.Google Scholar
  16. Levine, S., 1960, “Anoxic-ischemic encephalopathy in rats,” Am. J. Path. 36: 1–17.PubMedGoogle Scholar
  17. Oldendorf, W. H., 1971, “Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection,” Am. J. Physiol. 221: 1629–1639.PubMedGoogle Scholar
  18. Overton, E., 1895, “Über die osmotischen Eigenschaften der lebenden Pflanzen and Tierzelle,” Vierteljahresschr. Naturforsch. Ges. Zürich. 40: 159–201.Google Scholar
  19. Rapoport, S. I., 1970, “Effect of concentrated solutions on blood-brain barrier,” Am. J. Physiol. 219: 270–274.PubMedGoogle Scholar
  20. Rapoport, S. I., 1971, “The cortical acidic response to intravenous NaHCO3 and the nature of blood-brain barrier damage,” Intern. J. Neurosci. 2: 1–6.CrossRefGoogle Scholar
  21. Rapoport, S. I., 1973, “Evidence for reversible opening of the blood-brain barrier by osmotic shrinkage of the cerebrovascular endothelium and opening of the tight junctions. Relation to carotid arteriography,” in: Small Vessel Angiography. Imaging, Morphology, Physiology and Clinical Applications. S. K. Hilal, Ed. C. V. Mosby Company, St. Louis.Google Scholar
  22. Rapoport, S. I., Bachman, D. S., and Thompson, H. K., 1972a, “Chronic effects of osmotic opening of the blood-brain barrier in the monkey.” Science 176: 1243–1245.PubMedCrossRefGoogle Scholar
  23. Rapoport, S. I., Brightman, M. W. and Reese, T. S., 1973 “Reversible osmotic opening of the blood-brain barrier by opening tight junctions of cerebrovascular endothelium,” Biophys. Soc. 17th Ann. Meeting Abstr. 13: 230a.Google Scholar
  24. Rapoport, S. I., Hori, M., and Klatzo, I., 1972b, “Testing of a hypothesis for osmotic opening of the blood-brain barrier,” Am. J. Physiol. 223: 323–331.PubMedGoogle Scholar
  25. Rapoport, S. I. and Thompson, H. K., 1973, Osmotic opening of the blood-brain barrier in the monkey without associated neurological deficits, Science, 180: 971.PubMedCrossRefGoogle Scholar
  26. Reese, T. S. and Karnovsky, M. J., 1967, “Fine structural localization of a blood-brain barrier to exogenous peroxidase,” J. Cell. Biol. 34: 207–217.PubMedCrossRefGoogle Scholar
  27. Solomon, A. K., 1968, “Characterization of biological membranes by equivalent pores,” J. Gen. Physiol. 51: (5, pt. 2) 335s–364s.PubMedGoogle Scholar
  28. Steinwall, O., 1958, “An improved technique for testing the effect of contrast media and other substances on the blood-brain barrier,” Acta Radiol. 49: 281–284.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1972

Authors and Affiliations

  • Stanley I. Rapoport
    • 1
  1. 1.Laboratory of NeurophysiologyNational Institute of Mental HealthBethesdaUSA

Personalised recommendations