Abstract
Hemoglobin has been shown to inhibit brain Na+−K+-ATPase through an iron-dependent mechanism. Both hemoglobin and iron cause spontaneous peroxidation of brain lipids. Release of iron from the heme molecule in animal tissues is dependent on the activity of heme oxygenase. We hypothesized that inhibition of heme catabolism by heme oxygenase prevents the iron-mediated inhibition of Na+−K+-ATPase and might subsequently reduce the tissue damage. Therefore, we studied the effect of heme and tin-protoporphyrin, an inhibitor of heme oxygenase, on the activity of partially purified Na+−K+-ATPase from rat brain in the presence and absence of purified hepatic heme oxygenase. Heme alone at a concentration of 30 μM did not inhibit Na+−K+-ATPase. However, in the presence of heme oxygenase, heme inhibited Na+−K+-ATPase by 75%. Pretreatment of rats with SnCl2, a known inducer of heme oxygenase, reduced the basal activity of the brain Na+−K+-ATPase by 50%. Inhibition of heme oxygenase by tin-protoporphyrin (30 μM) prevented the inhibition of Na+−K+-ATPase which occurred in the presence of heme and heme oxygenase. It is concluded that suppression of heme oxygenase by tin-protoporphyrin might be a therapeutic approach to management of hemoglobin-associated brain injury following CNS hemorrhage.
Similar content being viewed by others
References
Edvinson, L., Hardebo, J. H., and Owman, C. 1978. Pharmacological analysis of 5-hydroxytriptamine receptors in isolated intracranial and extracranial vessels in cat and man. Circ. Res. 42:143–151.
Linder, M., and Alksne, J. P. 1978. Prevention of persisted cerebral smooth muscle contraction in response to whole blood. Stroke 9:472–477.
Zervas, N. T., Lavyne, M. H., and Neguro, M. 1975. Neurotransmitters and the normal and ischemic cerebral circulation. N. Engl. J. Med. 293:812–816.
Lobato, R. D., Martin, J., Salaices, M., Rico, M. L., and Sanchez, C. F. 1977. Effect of subarachnoid hemorrhage on contractile response and noradrenaline release evoked in cat cerebral arteries by histamine. J. Neurosurgery 55:543–549.
Toda, N., and Shimizu, K. 1980. Mechanism of cerebral arterial contraction induced by blood constituents. J. Neurosurgery 53:312–322.
Wellum, G. R., Irvine, T. W., Jr., and Zervas, N. T. 1980. Dose responses of cerebral arteries of the dog, rabbit, and man to human hemoglobin in vitro. J. Neurosurgery 53:486–490.
Wellum, G. R., Irvine, T. W., Jr., and Zervas, N. T. 1982. Cerebral vasoactivity of heme protein in vitro. J. Neurosurgery 56:777–778.
Sadrzadeh, S. M. H., Graf, E., Panter, S. S., Hallaway, P. E., and Eaton, J. W. 1984. Hemoglobin: a biologic fenton reagent. J. Biol. Chem. 259:14354–14356.
Sadrzadeh, S.M.H., Anderson, D.K., Panter, S.S., Hallaway, P.E., and Eaton, J.W. 1987. Hemoglobin potentiates central nervous system damage. J. Clin. Invest. 79:662–664.
Waters, A., and Harder, D.R. 1985. Altered membrane properties of cerebral vascular smooth muscle following subarachnoid hemorrhage: An electrophysiological study. I. Changes in resting membrane potential (Em) and effect on the electrogenic pump contribution to Em. Stroke 16:990–997.
Abraham, N.G., Friedland, M.L., and Levere, R.D. 1983. Heme metabolism in erythroid and hepatic cells. Pages 75–130 in Elmer, E.B. (ed.), Progress in hematology, Volume XIII, Grune & Stratton, Inc. New York.
Drummond, G.S., and Kappas, A. 1981. Prevention of neonatal hyperbiliburinemia by tin-protoporphyrin IX, a potent competitive inhibitor of heme oxidation. Proc. Natl. Acad. Sci. USA 68(10):6466–6470.
Abraham, N.G., Pinto, A., Levere, R.D., and Mullane, K.M. 1987. Identification of heme oxygenase and cytochrome P450 in the rabbit heart. J. Mol. Cell. Cardiol. 19:73–80.
Lowry, O.H., Rosenbrough, N.J., Farr, A.L., and Randall, R.J. 1951. Protein measurement with folin reagent. J. Biol. Chem. 193:265–275.
Jorgenson, P.L. 1974. Isolation of Na+−K+-ATPase. Methods Enzymol. 32:277–290.
Candia, O.A., Lanzetta, P.A., Alvorez, J.L., and Garzes, W. Inhibition of ionic transport and ATPase and activities by serotonin analogues in the isolated toad lens. 1980. Biochim. Biophys. Acta 602:389–400.
Hermsmeyer, K. 1976. Cellular basis for increased sensitivity of vascular smooth muscle in spontaneously hypertensive rats. Circ. Res. 38(Sup. II):53–57.
Van Breeman, C., Aaronson, P., and Loutzeniser, R., 1979. Sodium-calcium interactions in mammalian smooth muscle. Pharmacol. Rev. 30:167–208.
Willmore, L.J., Sypert, G.W., Munson, J.B., and Hord, R.W. 1978. Chronic focal epileptiform discharges induced by injection of iron into rat and cat cortex. Science 200:1501–1503.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Levere, R.D., Escalante, B., Schwartzman, M.L. et al. Role of heme oxygenase in heme-mediated inhibition of rat brain Na+−K+-ATPase: Protection by tin-protoporphyrin. Neurochem Res 14, 861–864 (1989). https://doi.org/10.1007/BF00964815
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00964815