Effects of epinephrine and amrinone on contractility and cyclic adenosine monophosphate generation of tumor necrosis factor alpha-exposed cardiac myocytes

Kumar, Anand; Kosuri, Raju; Kandula, Prasad; Dimou, Cathy; Allen, Jill N.; Parrillo, Joseph E.

doi:10.1097/00003246-199902000-00032

Cited by 26 publications

(10 citation statements)

References 28 publications

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“…Coincubation of TNF-␣, IL-1␤, synergistic combinations of the two, or human septic serum with competitive inhibitors of NO synthase (NOS) attenuates or prevents depressant responses in isolated cardiac myocytes. TNF-␣ also blunts generation of cAMP and contractile response to catecholamine stimulation in these myocytes (18). This observation is congruent with evidence of sepsis-associated cardiovascular resistance to adrenergic stimulation noted in a variety of clinical and experimental studies of sepsis and septic shock (15,16,20,26,33).…”

supporting

confidence: 80%

“…We have previously demonstrated that TNF-␣ exposure results in an early effect of attenuation of ␤-adrenoreceptor-mediated increases in myocyte contractility and cAMP generation (18). Bick et al (3) have also shown that short-term neonatal rat cardiac myocyte exposure to TNF-␣ results in blunted contractility and cAMP response to isoproterenol but that responses to forskolin are preserved.…”

Section: Discussionmentioning

confidence: 95%

“…This depressant activity (inclusive of TNF-␣) has been shown to be mediated, in part, by NO (generated by a calciumdependent NOS) and cGMP (17). An adrenoreceptor signaling defect in response to catecholamine stimulation has also been implicated in early TNF-␣-mediated dysfunction of isolated cardiac myocyte contraction (3,18). In this study, we sought to determine whether TNF-␣ may act through multiple mechanisms to generate depression of cardiac myocyte contraction and whether these mechanisms are NO-dependent or independent.…”

Section: Discussionmentioning

confidence: 99%

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Nitric oxide-dependent and -independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility

Kumar

Paladugu²,

Mensing³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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supporting

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Nitric oxide-dependent and -independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility

Kumar

Paladugu²,

Mensing³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In vitro tests of PDE inhibitors on mouse and human macrophages showed inhibition of TNF-␣ and interleukin production (36,37). The cytokines are known to be responsible for cardiac depression and capillary leak syndrome during septicaemia and after cardiopulmonary bypass (7,10). In adult patients after cardiopulmonary bypass and during septic shock, enoximone reduced endotoxin and TNF-␣ levels compared with dobutamine-treated patients (30,38).…”

Section: Discussionmentioning

confidence: 99%

Cardiac rescue with enoximone in volume and catecholamine refractory septic shock

Ringe

Varnholt

Gaedicke

2003

Pediatric Critical Care Medicine

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In December 2000 and February 2001, two children with suspected meningococcal disease were admitted to our pediatric intensive unit. Their Glasgow Meningococcal Septicaemia Prognostic score was 12 points. General treatment including antibiotics, steroids in case of meningitis, and fluid replacement, was performed. Despite appropriate volume replacement, intubation and ventilation, noradrenaline and adrenaline continuous infusions < or =1.0 microg/kg/min, and additional bolus infusions, cardiac output deteriorated within minutes in both children. Calcium and bicarbonate were given without sustained effect. Echocardiography demonstrated no pericardial effusion and shortening fraction was <10%. External cardiac massage had to be performed immediately in one case for electromechanical uncoupling. Both patients received a bolus of enoximone 2 mg/kg and 5 mg/kg body weight, respectively, followed by a continuous infusion of 20-23 microg/kg/min. Thereafter, both children had an adequate blood pressure and their shortening fraction increased to >30%. Within minutes, the catecholamine infusion could be reduced in both patients. The children completely recovered from their life-threatening situations. In patients with severe prolonged catecholamine and volume refractory endotoxin shock in Waterhouse-Friderichsen syndrome, even with electromechanical uncoupling and complete myocardial arrest, enoximone can immediately restore myocardial contractility.

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“…However, some studies have suggested that this also occurs acutely after exposure to cytokines (Figure 2). In isolated mammalian myocytes, within minutes of exposure to cytokines such as TNF-␣, IL-1␤, and IL-6, there is an inhibition of catecholamine-stimulated contractility, 71,75 cAMP generation, 71 and I Ca augmentation. 75,76 The mechanism for this defect in ␤-AR signal transduction is not clear, although one study 76 suggested a mechanism unrelated to alterations in ␤-AR binding, adenylyl cyclase (AC) activity, or cAMP.…”

Section: Other Mechanismsmentioning

confidence: 99%

Cytokine-Induced Modulation of Cardiac Function

Prabhu

2004

Circulation Research

345

267

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Abstract-Cytokines act in an autocrine and/or paracrine fashion to induce a diverse variety of biological responses.Several cardiac diseases are associated with cytokine activation, and such activation significantly influences several physiologic parameters, including cardiac mechanical function. This review summarizes the current concepts regarding the modulation of myocardial function by cytokines and provides rationale for the sometimes-conflicting results in the literature regarding underlying mechanisms and patterns of dysfunction. Although traditionally considered cardiodepressant mediators, contractile responses are complex and bimodal, with an early response (within minutes) of variable direction, stimulatory or depressant, depending on the ambient physiologic milieu and relative contributions of the underlying signaling pathways that are activated. These pathways include sphingomyelinase-, nitric oxide (NO)-, and phospholipase A2-dependent signaling with resultant combined effects on contraction and the Ca 2ϩ transient. This is subsequently followed by a profoundly cardiodepressant late response lasting hours to days, depending on the production of secondary mediators and the combined influence of NO generated from inducible NO synthase, reactive oxygen species, and alterations in ␤-adrenergic receptor signaling. The interrelationships between these pathways and the time-dependence of their activation are important considerations in the evaluation of cytokine-dependent dysfunction during both acute cardiac injury and chronic cardiac pathologies.

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Effects of epinephrine and amrinone on contractility and cyclic adenosine monophosphate generation of tumor necrosis factor alpha-exposed cardiac myocytes

Cited by 26 publications

References 28 publications

Nitric oxide-dependent and -independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility

Nitric oxide-dependent and -independent mechanisms are involved in TNF-α-induced depression of cardiac myocyte contractility

Cardiac rescue with enoximone in volume and catecholamine refractory septic shock

Cytokine-Induced Modulation of Cardiac Function

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