The role of nitric oxide in cardiac depression induced by interleukin‐1β and tumour necrosis factor‐α

Abstract

1 Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1p and tumour necrosis factor-x (TNF-x). These cytokines depress cardiac mechanical function by a mechanism which is not well defined.2 Bacterial endotoxin or cytokines cause the expression of Ca2"-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-lp plus TNF-a in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation.3 Rat isolated working hearts perfused with IL-1p plus TNF-a showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-ip plus TNF-a was first apparent after 1 h of perfusion; no early (15min) cardiac depressant actions were seen. 4 The competitive inhibitor of Ca2"-dependent and Ca2"-independent NO synthases, N0-nitro-Larginine methyl ester (L-NAME, 3#M) when given concurrently with IL-lp plus TNF-x prevented the loss in contractile function such that these hearts after 2h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 plus TNF-x. The protective action of L-NAME in the presence of cytokines was concentration-dependent and was not seen at a higher concentration (10 pM) due to the significant reduction in coronary flow observed at this concentration.5 In contrast, when L-NAME (3 1M) was given in the absence of IL-lP plus TNF-x it depressed contractile function over the 2 h perfusion period by significantly reducing coronary flow. 6 Inhibition of protein synthesis with cycloheximide (Cx) abolished the loss in function that occurred over 2h in both control and IL-il plus TNF-a-treated hearts.7 Inducible, Ca2"-independent NO synthase activity was not observed in freshly isolated hearts but was observed in control hearts perfused for 2 h in vitro and was doubled in hearts perfused with IL-IP plus TNF-a. Cx prevented the expression of Ca2"-independent NO synthase in both control and cytokine-treated hearts.8 In summary, these results suggest that the depression of myocardial function by IL-lP plus TNF-a is mediated, at least in part, by induction of Ca2"-independent NO synthase activity in the heart.

Early sepsis does not stimulate reactive oxygen species production and does not reduce cardiac function despite an increased inflammation status

“…The high levels of TNF‐ α and IL‐1 β mRNAs should have depressed the cardiac mechanical activity (Schulz et al. 1995). This was not the case.…”

Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

“…The mechanism(s) by which IL-1␤ and TNF-␣ induce contractile dysfunction has also been linked to NO and changes in cellular calcium handling (31). In addition, inhibition of the sphingomyelin signaling pathway abrogated TNF-␣͞IL-1␤-induced myocardial contractile dysfunction (22).…”

“…IL-1␤ and TNF-␣ have also been implicated in the pathogenesis of human myocardial suppression in sepsis (30,31). The mechanism(s) by which IL-1␤ and TNF-␣ induce contractile dysfunction has also been linked to NO and changes in cellular calcium handling (31).…”

Tumor-Necrosis-Factor-.ALPHA.-Gene-Deficient Mice Have Improved Cardiac Function Through Reduction of Intercellular Adhesion Molecule-1 in Myocardial Infarction

“…33 After MI, TNF-is induced by invading inflammatory cells and the infarcted and non-infarcted cardiac myocytes produce a high level of NO and NO products, such as peroxynitrite, especially in the infarcted and border zone areas. 34,35 The concentrations of NO and TNF-in patients with congestive heart failure increase in proportion to the severity of heart failure, indicating a role of TNF-in enhanced systemic and local production of NO. 36 Our study is the first to demonstrate weaker expression of 3-nitrotyrosine in infarcted myocardium in KO mice than in WT mice, and this attenuation of 3-nitrotyrosine expression in the KO mice is at least partly attributed to less inflammatory cells invading after MI.…”