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

1 Departments of Pediatrics and Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and 2 Division of Critical Care, Children's Hospital Medical Center, Cincinnati, Ohio 45229 Proinflammatory cytokines (interleukin-1 , tumor necrosis factor- , and interferon- ; Cytomix) depress myocardial contractile work partially by stimulating expression of inducible nitric oxide (NO) synthase (iNOS). Because NO and peroxynitrite inhibit myocardial O 2 consumption (M O 2 ), 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 M O 2 . Cardiac efficiency (work/M O 2 ) 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 M O 2 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 M O 2 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. inducible nitric oxide synthase; peroxynitrite; mercaptoethylguanidine; dexamethasone; isolated heart