Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock.
1. We investigated the effects of recombinant human erythropoietin (rh-EPO) in splanchnic artery occlusion (SAO) shock. Sham operated animals were used as controls. Survival rate, mean arterial blood pressure (MAP), serum Tumor Necrosis Factor (TNF-alpha), plasma nitrite/nitrate concentrations, red blood cell (RBC) count, blood haemoglobin (Hb), the responsiveness of aortic rings to phenylephrine (PE, 1 nM-10 microM) and the activity of inducible nitric oxide synthase (iNOS) were studied. 2. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrations, increased plasma nitrite/nitrate levels (60+/-9.5 microM; sham shocked rats= 2+/-0.4 microM), decreased MAP, unchanged RBC count and blood Hb and enhanced iNOS activity in the aorta. Moreover aortic rings from shocked rats showed a marked hyporeactivity to PE. 3. Rh-EPO (25, 50 and 100 U 100 g(-1), 5 min following the onset of reperfusion) increased survival rate (70% at 4 h of reperfusion with the highest dose), reduced plasma nitrite/nitrate concentrations (10.3+/-3.3 microM), increased MAP, did not change RBC count and blood Hb, and inhibited iNOS activity in thoracic aortae. Furthermore rh-EPO, either in vivo or in vitro (10 U for 1 h in the organ bath), restored to control values the hyporeactivity to PE. Finally rh-EPO inhibited the activity of iNOS in peritoneal macrophages activated with endotoxin. 4. Our data suggest that rh-EPO protects against SAO shock by inhibiting iNOS activity.
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Institute of Pharmacology, School of Medicine, University of Messina, Italy. squadrito@csnet.it
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D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003251:Constriction, Pathologic / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012769:Shock / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology*; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat