title: Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock.
abstract: Endotoxin and proinflammatory cytokines induce nitric oxide synthase (NOS), and nitric oxide (NO) plays an important role in promoting endotoxin shock. However, the role of NOS in endotoxemic cardiac contractile dysfunction is not defined. To determine whether endotoxemic cardiac contractile dysfunction involves NOS, the present study used a rat model of endotoxemia without shock and examined the effects of glucocorticoids (dexamethasone, a potent inhibitor of inducible NOS, iNOS, expression), isoform nonselective NOS inhibitor (NG-monomethyl-L-arginine, L-NMA) and iNOS selective inhibitor (S-methylisothiourea sulfate, SMT) on cardiac contractile dysfunction. A sublethal dose of endotoxin (from Salmonella typhimurium, .5 mg/kg, i.p.) was given to adult rats, and left ventricular developed pressure (LVDP) examined by Langendorff technique was attenuated in hearts isolated at 4 or 6 h (66.7 +/- 3.4 and 60.3 +/- 5.5 mmHg, respectively, p < .05 vs. 102 +/- 2.4 mmHg in saline control) after endotoxin treatment. Pretreatment of rats with dexamethasone (4.0 mg/kg, i.v., -30 min) partially abolished endotoxin-induced contractile dysfunction at 6 h (LVDP 87.6 +/- 6.8 mmHg, p < .05 vs. endotoxin alone at 6 h). However, pretreatment with L-NMA (30 mg/kg, i.v., -5 min) or SMT (5.0 mg/kg, i.v., -1 min) failed to prevent the contractile dysfunction. Moreover, infusion of L-NMA or SMT in vitro could not restore contractile function in hearts isolated at 6 h after endotoxin treatment. In contrast, inhibition of NOS with L-NMA or SMT in vitro further attenuated coronary flow in endotoxin-treated hearts. Thus, endotoxemic cardiac contractile dysfunction in this non-shock rat model may not involve NOS, and inhibition of NOS may deteriorate coronary perfusion in endotoxemic heart.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.forename: L
authors.initials: L
authors.lastname: Ao
authors.forename: J M
authors.initials: JM
authors.lastname: Brown
authors.forename: D A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: A
authors.initials: A
authors.lastname: Banerjee
authors.forename: A H
authors.initials: AH
authors.lastname: Harken
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D009200:Myocardial Contraction; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine
chemical_list: D001120:Arginine; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D007550:Isothiuronium; D019001:Nitric Oxide Synthase; C092506:N(G)-monomethylarginine acetate; D019323:omega-N-Methylarginine; C027744:S-methylisothiopseudouronium