Physiological targets of superoxide anion and hydrogen peroxide in reperfusion injury.
Current dogma associates reperfusion injury with the introduction of reactive oxygen species (ROS) into the ischemic tissue. The sources of ROS under discussion are xanthine oxidase in the endothelium of small vessels and/or invaded polymorphonuclear leukocytes (PMN). The beneficial effects of both superoxide dismutase and catalase suggest an involvement of superoxide anions and hydrogen peroxide in this pathophysiological process, without describing the targets of their action. In our work we demonstrate that these two ROS effectively interact with two enzymes. Superoxide anions inhibit soluble guanylate cyclase. Its product, cGMP, is considered to antagonize platelet activation and to cause smooth muscle relaxation. Thus O2- can intensify platelet aggregability and small vessel occlusion. Similar effects are elicited by H2O2, which shifts the dose response curve of several agonists towards smaller concentrations by activating cyclooxygenase. This enzyme provides the substrate for thromboxane synthase which generates TxA2, the most potent physiologically occurring platelet aggregating and smooth muscle contacting agonist. These results lead us to the suggestion that the influence of the oxidative burst of PMN in the phenomenon of reperfusion injury should be reconsidered.
Ullrich
V
V
Faculty of Biology, University of Konstanz, F.R.G.
Brüne
B
B
Hecker
G
G
Schmidt
K U
KU
Mülsch
A
A
Busse
R
R
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D001792:Blood Platelets / Q000201:enzymology; D002248:Carbon Monoxide / Q000378:metabolism; D002498:Centrifugation; D002855:Chromatography, Thin Layer; D006162:Guanylate Cyclase / Q000097:blood / Q000302:isolation & purification; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D010974:Platelet Aggregation; D015427:Reperfusion Injury / Q000378:metabolism*; D012995:Solubility; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D001095:Arachidonic Acids; D013481:Superoxides; D016718:Arachidonic Acid; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase