Selective NOS inhibition restores myocardial contractility in endotoxemic rats; However, myocardial NO content does not correlate with myocardial dysfunction

The role of nitric oxide (NO) in lipopolysaccharide (LPS)-induced myocardia l dysfunction remains controversial as some investigators concluded that in hibition of NO synthesis improves left ventricular (LV) contractility, wher eas others did not. We investigated the relationship between LPS-induced LV dysfunction and LV NO production. We postulated that high myocardial NO co ncentrations would correspond to decreased contractility and low NO concent rations would correspond to recovery. In a rat model of endotoxemia, we use d the isolated papillary preparation to assess inotropic dysfunction. We me asured LV NO content and hemodynamics at baseline, 4, 16, and 48 h after LP S administration. LPS caused a decrease in LV contractility at 16 h with re covery at 48 h. Myocardial NO levels were elevated at all time periods. How ever, at 48 h in spite of normalization of LV contractility, myocardial NO content remained elevated. Pretreatment of LPS animals with the nonselectiv e nitric oxide synthase (NOS) inhibitor N-G-nitro-L-arginine methyl ester ( L-NAME) worsened LV contractility, decreased LV NO content, and increased m ortality. However, pretreatment with the relatively selective inducible NOS (iNOS) inhibitor S-methylisothiourea sulfate (SMT) restored LV contractili ty. Myocardial NO content in the SMT was lower than that of the LPS only gr oup, but higher than the L-NAME group. We conclude that SMT is beneficial t o myocardial contractility in this model of endotoxemia, whereas pretreatme nt with L-NAME is associated with further deterioration of contractility an d increased mortality. Moreover, our data indicate that high myocardial NO concentrations do not necessarily correlate with decreased contractility.