title: Distribution of NOS isoforms in a porcine endotoxin shock model.
abstract: Sepsis is a major cause of morbidity and mortality. NO, an endogenous vasodilator, has been associated with the hypotension, catecholamine hyporesponsiveness, and myocardial depression of septic shock. Although iNOS is thought to be responsible for the hypotension and loss of vascular tone occurring several hours after endotoxin administration, little is known on the effects of constitutive eNOS on LPS-induced organ dysfunction. This study assessed the distribution of eNOS and iNOS in various vascular beds in conscious pigs challenged with LPS. Cardiac and regional hemodynamic parameters were recorded over 8 h in the presence and absence of aminoguanidine, a rather selective inhibitor of iNOS activity, and N-methyl-L-arginine, a nonspecific NOS inhibitor. Our data show that LPS-induced cardiac depression was associated with coronary, renal, and mesenteric vasoconstrictions and a hepatic vasodilatation. LPS also induced increases in eNOS in the heart and lungs, whereas iNOS was mostly detected in the liver. Nitrotyrosine formation was mainly detected in the lungs, with traces in the kidney, liver, and gut. Accordingly, our results suggest that the early decrease in blood pressure and cardiac depression are likely due to activated eNOS, whereas both isoforms are involved in the hepatic vasodilation. In contrast, carotid, coronary, mesenteric, and renal vasoconstrictions were significant at 5 and/ or 6 h after LPS infusion, suggesting that NO is not the primary mediator, facilitating and/or unmasking the release of vasoconstrictor mediators. Consequently, developing newer tissue- or isoform-specific NOS inhibitors can lead to novel therapeutic agents in septic shock.
authors.affiliation: The University of Texas Medical School at Houston, Department of Anesthesiology, 6431 Fannin, MSB 5.020, Houston, TX 77030-1503, USA. Marie-Francoise.Doursout@uth.tmc.edu
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Doursout
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oguchi
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Fischer
authors.forename: YangYan
authors.initials: Y
authors.lastname: Liang
authors.forename: Brice
authors.initials: B
authors.lastname: Chelly
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Hartley
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Chelly
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009928:Organ Specificity / Q000187:drug effects; D012772:Shock, Septic / Q000139:chemically induced / Q000201:enzymology*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D007527:Isoenzymes; D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C004479:pimagedine