Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock

Abstract

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‐α), plasma nitrite/nitrate concentrations, red blood cell (RBC) count, blood haemoglobin (Hb), the responsiveness of aortic rings to phenylephrine (PE, 1 nM–10 μM) and the activity of inducible nitric oxide synthase (iNOS) were studied. 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‐α concentrations, increased plasma nitrite/nitrate levels (60±9.5 μM; sham shocked rats=2±0.4 μM), 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. 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 μM), 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. Our data suggest that rh‐EPO protects against SAO shock by inhibiting iNOS activity. British Journal of Pharmacology (1999) 127, 482–488; doi:10.1038/sj.bjp.0702521