NITRIC-OXIDE SYNTHASE IS NOT INVOLVED IN CARDIAC CONTRACTILE DYSFUNCTION IN A RAT MODEL OF ENDOTOXEMIA WITHOUT SHOCK

Endotoxin and proinflammatory cytokines induce nitric oxide synthase ( NOS), and nitric oxide (NO) plays an important role in promoting endot oxin shock. However, the role of NOS in endotoxemic cardiac contractil e dysfunction is not defined. To determine whether endotoxemic cardiac contractile dysfunction involves NOS, the present study used a rat mo del of endotoxemia without shock and examined the effects of glucocort icoids (dexamethasone, a potent inhibitor of inducible NOS, iNOS, expr ession), isoform nonselective NOS inhibitor (N-G-monomethyl-L-arginine , L-NMA) and iNOS selective inhibitor (S-methylisothiourea sulfate, SM T) 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 a nd 60.3+/-5.5 mmHg, respectively, p <.05 vs. 102+/-2.4 mmHg in saline control) after endotoxin treatment. Pretreatment of rats with dexameth asone (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. endo toxin 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 contra ctile dysfunction. Moreover, infusion of L-NMA or SMT in vitro could n ot restore contractile function in hearts isolated at 6 h after endoto xin treatment. In contrast, inhibition of NOS with L-NMA or SMT in vit ro further attenuated coronary flow in endotoxin-treated hearts. Thus, endotoxemic cardiac contractile dysfunction in this non-shock rat mod el may not involve NOS, and inhibition of NOS may deteriorate coronary perfusion in endotoxemic heart.