Nitric oxide-dependent and -independent mechanisms are involved in TNF-␣-induced depression of cardiac myocyte contractility. Am J Physiol Regul Integr Comp Physiol 292: R1900-R1906, 2007. First published January 18, 2007; doi:10.1152/ajpregu.00146.2006.-Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This response is mediated, in part, through circulating TNF-␣-induced, nitric oxide-dependent, depression of basal myocyte contractility. Other mechanisms of early myocardial dysfunction involving decreased response to adrenergic stimulation may exist. This study evaluated the presence and nitric oxide dependence of impaired adrenergic response to TNF-␣ in in vitro cardiac myocytes. The contraction of electrically paced neonatal rat cardiac myocytes in tissue culture was quantified using a closedloop video tracking system. TNF-␣ induced depression of baseline contractility over the first 20 min of cardiac myocyte exposure. This effect was blocked by N-methyl-arginine (NMA), a nitric oxide synthase inhibitor, in all studies. Contractile and cAMP response to increasing concentrations of isoproterenol was deficient in cardiac myocytes exposed to TNF-␣ regardless of the presence of NMA. In contrast, increasing concentrations of forskolin (a direct stimulant of adenylate cyclase) and dibutyryl cAMP (a metabolically active membrane-soluble analog of cAMP) completely reversed TNF-␣-mediated depression, though only in the presence of NMA. Forskolin-stimulated cAMP generation remained intact regardless of NMA. Increasing concentrations of exogenous calcium chloride, unlike other inotropic agents, corrected TNF-␣-mediated defects of contractility independent of the presence of NMA. These data suggest that TNF-␣ exposure is associated with a second nitric oxide-independent but calcium-dependent early depressant mechanism that is manifested by reduced contractile and cAMP response to ␤-adrenergic stimulation. sepsis; septic shock; adrenoreceptor; myocardial depression; myocyte; heart; myocardial depressant substance; cytokine THE NORMAL CARDIAC RESPONSE to septic shock involves biventricular dilatation and decreased ejection fractions (14,24,25). Clinically, septic myocardial depression is also reflected by a suboptimal stroke volume response to fluid resuscitation (22) and infusion of exogenous catecholamines (15,20,32).The causal role of circulating factors in myocardial depression in human septic shock is now well established (21,(27)(28)(29)31). Measurements of isolated cardiac myocyte contraction in the presence of serum from patients with acute septic shock demonstrate a depression of maximum extent and peak velocity of myocyte shortening that correlates quantitatively and temporally with depression of the patient's left ventricular ejection fraction as measured by radionuclide ventriculography (27,31). We have demonstrated that this depressant activity represents a synergistic combination of low-circulating concentrations of the proinflammatory cytokin...

These data demonstrate that depression of in vitro cardiac myocyte contraction induced by proinflammatory cytokines and septic serum can be blocked by TGF-beta1. TGF-beta1 may have potential as therapy for sepsis-associated myocardial depression in humans.

Sepsis and septic shock, the systemic immunologic and pathophysiologic response to overwhelming infection, are associated with perturbation of a variety of metabolic cell pathways and with multiple organ failure (MOF) including cardiac depression. This depression has been attributed to the effect of several circulating and locally produced proinflammatory mediators. Recent data suggest that bacterial nucleic acids can produce profound systemic inflammatory responses characterized by circulatory shock in intact animals. In this study, bacterial DNA and RNA derived from pathogenic clinical S. aureus and E. coli isolates are shown to induce early concentration-dependent depression of maximum extent and peak velocity of contraction of electrically paced neonatal rat ventricular myocytes in culture. Significant but more modest depression was generated by a nonpathogenic E. coli isolate. Pretreatment with a DNase or RNase abrogated this effect. Further, synthetic, double-stranded RNA (dsRNA) also induced concentration-dependent depression of myocyte contraction, with the effect also being prevented by pretreatment with RNase. These data suggest that bacterial DNA and RNA may contribute to myocardial depression during bacterial sepsis and septic shock.

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