Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism

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Abstract
Proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α, and interferon-γ; Cytomix) depress myocardial contractile work partially by stimulating expression of inducible nitric oxide (NO) synthase (iNOS). Because NO and peroxynitrite inhibit myocardial O2 consumption (MV˙o2), we examined whether this mechanism contributes to reduced cardiac work. In control isolated working rat hearts, cardiac work was stable for 60 min, followed by a decline from 60 to 120 min, without change in MV˙o2. Cardiac efficiency (work/MV˙o2) was therefore reduced from 60 to 120 min. Cytomix shortened the onset (within 20–40 min) and enhanced the depression in cardiac work and efficiency and inhibited MV˙o2 after 80 min. Mercaptoethylguanidine (MEG), an iNOS inhibitor and peroxynitrite scavenger, or the glucocorticoid dexamethasone (Dex) abolished the effects of Cytomix. iNOS expression was increased 10-fold by Cytomix and abolished by Dex but not MEG. That cytokine-induced depression in cardiac work precedes the reduction in MV˙o2 suggests, at least in the early response, that NO and/or peroxynitrite may not impair heart function by inhibiting mitochondrial respiration but reduce the heart’s ability to utilize ATP for contractile work.