Hemorrhagic shock resuscitation affects early and selective mesenteric artery endothelial function through a free radical-dependent mechanism.
Mesenteric ischemia/reperfusion occurring during hemorrhagic shock and resuscitation (H/R) induces a systemic inflammatory response and damages endothelial cells. Our aim was to investigate whether H/R affects selectively mesenteric vascular reactivity and the roles of free radicals and inducible nitric oxide (NO) synthase (iNOS) in these changes. Rats subjected to H (30 min)/R (60 min) in the presence or absence of the free radical scavenger N-2 mercaptopropionyl glycine (MPG), or the specific inhibitor of iNOS [(3) N-(3-aminomethyl)benzyl) acetaminide; 1400W] were studied. Saline requirements to maintain systemic blood pressure during R (53.4 +/- 5.2 mL/kg/h) were reduced by MPG (26.2 +/- 3.1) and 1400W (37.5 +/- 4.1). H/R reduced maximal mesenteric arteries relaxation to acetylcholine (sham: 70% +/- 5%, H/R: 21% +/- 3%) and this impairment was prevented by MPG (66% +/- 10%) and reduced by 1400W (49% +/- 9%). H/R did not affect the endothelium-independent relaxations. Maximal responses to phenylephrine were reduced in mesenteric arteries by H/R (3.6 +/- 0.5 mN/mm vs. sham 6.5 +/- 0.5), this impairment was prevented by 1400W and MPG. No impaired response to acetylcholine was detected in skeletal muscle arteries. H/R was associated with an increased production of TNF-alpha (169 +/- 8.5 ng/mL vs. sham 38 +/- 5 ng/mL), and this was reduced to 75 +/- 8 ng/mL in MPG-treated rats. Total intestinal content of iNOS mRNA was also increased by H/R and this increase was partly reduced by treatment with MPG. H/R induces an early and selective mesenteric endothelial cell dysfunction through a mechanism that involves oxygen-derived free radicals and NO produced by iNOS. H/R is associated with a mesenteric hyporeactivity through an induction of NOS and may be prevented by scavenging free radicals. This early impairment in endothelial function is associated with a local inflammatory response.
Savoye
Guillaume
G
INSERM E9920, IFRMP 23, Department of Pharmacology, Rouen University Medical School, 76183 Rouen, France. guillaume.savoye@chu-rouen.fr
Tamion
Fabienne
F
Richard
Vincent
V
Varin
Rémi
R
Thuillez
Christian
C
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology*; D016166:Free Radical Scavengers; D005609:Free Radicals; D006439:Hemodynamics; D007249:Inflammation; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology*; D008981:Molsidomine / Q000031:analogs & derivatives / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010100:Oxygen / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D012151:Resuscitation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation
D016166:Free Radical Scavengers; D005609:Free Radicals; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; C002385:linsidomine; D012313:RNA; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000109:Acetylcholine; D010100:Oxygen