Prostaglandin E1 reduces ischemia/reperfusion injury by normalizing nitric oxide and superoxide release.
To test the effects of prostaglandin E1 on 2.5 h of ischemia followed by 2 h of reperfusion, continuous nitric oxide measurements (electrochemical) were correlated with intermittent assays of superoxide and peroxynitrite levels (chemiluminescence) and ischemia/reperfusion injury in rabbit adductor magnus muscle. Administering prostaglandin E1 (1 microg/kg) before or during ischemia/reperfusion caused normalization of the release of nitric oxide, superoxide, and peroxynitrite to slightly above preischemic levels. This pattern was dramatically different from that observed during ischemia/reperfusion alone, where nitric oxide concentration increased three times above its basal level. Normalization of constitutive nitric oxide synthase activity in the presence of prostaglandin E1 was associated with a significant reduction of superoxide and peroxynitrite production and subsequent reduction of ischemia/reperfusion injury. At 2 h of reperfusion, vasoconstriction associated with ischemia/reperfusion injury was eliminated, and edema was significantly mollified but still apparent. Prostaglandin E1 treatment does not directly inhibit constitutive nitric oxide synthase, like the inhibitor N(omega)-monomethyl-L-arginine. Some phenomenon associated with ischemia turns on endothelial constitutive nitric oxide synthase to start transforming L-arginine and oxygen into nitric oxide, but prostaglandin E1 seems to inhibit this phenomenon. Thus, essential local L-arginine pools are not depleted, and normal basal levels of essential nitric oxide are maintained, whereas cytotoxic superoxide and peroxynitrite production by L-arginine-deficient constitutive nitric oxide synthase is prevented.
Huk
I
I
Department of Vascular Surgery, University of Vienna, Austria.
Brovkovych
V
V
Nanobashvili
J
J
Neumayer
C
C
Polterauer
P
P
Prager
M
M
Patton
S
S
Malinski
T
T
D000109:Acetylcholine / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011817:Rabbits; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D009566:Nitrates; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000527:Alprostadil; D000109:Acetylcholine