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, I nM-10 mu M) 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 mu M; sham shocked rats = 2 +/- 0.4 mu M), 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 mu M), 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.