Role of heme oxygenase in heme-mediated inhibition of rat brain Na+-K+-ATPase: protection by tin-protoporphyrin.
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 microM 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 microM) 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.
Levere
R D
RD
Department of Medicine, New York Medical College, Valhalla 10595.
Escalante
B
B
Schwartzman
M L
ML
Abraham
N G
NG
D000818:Animals; D001921:Brain / Q000201:enzymology*; D004790:Enzyme Induction / Q000187:drug effects; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D014001:Tin / Q000494:pharmacology; D017971:Tin Compounds
D008665:Metalloporphyrins; D011166:Porphyrins; D011524:Protoporphyrins; D017971:Tin Compounds; C023599:stannous chloride; D006418:Heme; D014001:Tin; C032628:tin protoporphyrin IX; D006899:Mixed Function Oxygenases; D006419:Heme Oxygenase (Decyclizing); D000254:Sodium-Potassium-Exchanging ATPase