Protamine-induced Cardiotoxicity Is Prevented by Anti-TNF-α Antibodies and Heparin

2001 ◽  
Vol 95 (6) ◽  
pp. 1389-1395 ◽  
Author(s):  
Dmitry Pevni ◽  
Inna Frolkis ◽  
Adrian Iaina ◽  
Yoram Wollman ◽  
Tamara Chernichovski ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Tnf Alpha ◽  
Control Group ◽  
Lv Function ◽  
Heparin Group ◽  
Necrosis Factor Alpha ◽  
Rat Hearts ◽  
Factor Alpha

Background We investigated the role of tumor necrosis factor alpha (TNF-alpha) in protamine-induced cardiotoxicity and the possibility of preventing or decreasing this effect by anti TNF-alpha antibodies and heparin. Methods Isolated rat hearts were perfused for 60 min with Krebs-Henseleit solution (KH). The control group was perfused with KH alone, the KH > protamine > KH group was treated from the 20th to the 40th minute with protamine, and the KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF group was treated the same as the KH > protamine > KH group but with anti-TNF-alpha antibodies added throughout perfusion. The KH + heparin > protamine + heparin > KH + heparin group was treated the same as the KH > protamine > KH group but with heparin added to KH throughout perfusion. The KH > protamine > KH + heparin was perfused the same as the KH> protamine > KH group but with heparin added to KH for the last 20 min. Left ventricular (LV) function and coronary flow were measured every 10 min. TNF-alpha was measured in the coronary sinus effluent. Left ventricular TNF messenger RNA was determined in the control and KH > protamine > KH groups at baseline and after the 40-min perfusion. Results Protamine caused a significant decrease of peak systolic pressure and dP/dt (to 25% of baseline). Significant amounts of TNF-alpha in the effluent in the KH > protamine > KH group (102.3 +/- 15.5 pg/min) and TNF messenger RNA expression in left ventricular samples were detected. TNF-alpha was below detectable concentrations in the control, KH + anti-TNF > protamine + anti-TNF > KH + anti-TNF, and KH + heparin > protamine + heparin > KH + heparin groups. TNF-alpha concentrations correlated with depression of LV peak systolic pressure (r = 0.984; P = 0.01) and first derivate of the increase of LV pressure (r = 0.976; P = 0.001). Heparin improved LV recovery and decreased protamine-induced TNF-alpha release (KH > protamine > KH + heparin group). Conclusions Anti-TNF-alpha antibodies and heparin prevent protamine-induced TNF-alpha release and depression of LV function. Heparin improves protamine-induced depression of cardiac function.

Serum tumor necrosis factor-alpha does not mediate endotoxin-induced myocardial depression in rabbits

1996 ◽  
Vol 270 (2) ◽  
pp. H485-H491 ◽  
Author(s):  
Y. Nishikawa ◽  
J. Mathison ◽  
W. Y. Lew
Keyword(s):  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Control Group ◽  
Lv Function ◽  
Necrosis Factor Alpha ◽  
Systolic Volume ◽  
End Diastolic Volume ◽  
End Systolic Volume ◽  
Factor Alpha ◽  
Necrosis Factor

Tumor necrosis factor-alpha (TNF-alpha) is an endogenous mediator for several effects of endotoxin. To evaluate whether TNF-alpha mediates endotoxin-induced left ventricular (LV) dysfunction, we measured LV function (sonomicrometers) and serum TNF-alpha (cytolytic assay) in anesthetized rabbits given endotoxin (100 micrograms/kg iv). In the control group (n = 8), systolic depression (defined by a > 10% increase in end-systolic volume at a matched end-systolic pressure) developed in four rabbits and diastolic dilation (> 10% increase in end-diastolic volume at a matched end-diastolic pressure) developed in three rabbits. Neither the increase in end-systolic volume nor the increase in end-diastolic volume correlated with the increase in TNF-alpha, which reached a peak of 2,875 +/- 762 U/ml. In a second group of rabbits (n = 7), a goat polyclonal anti-rabbit antibody to TNF-alpha was given 30-60 min before endotoxin. Anti-TNF-alpha antibody alone did not alter LV function. Although the TNF-alpha response to endotoxin was effectively blunted (peak TNF-alpha remained < 100 U/ml), all seven rabbits developed systolic depression (P = 0.08 compared with control group) and diastolic dilation (P = 0.03). We conclude that serum TNF-alpha does not mediate endotoxin-induced LV systolic depression or diastolic dilation in this model.

scholarly journals Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin- induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3337-3343 ◽  
Author(s):  
JB Weinberg ◽  
SN Mason ◽  
TS Wortham
Keyword(s):  
Mrna Expression ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Nonspecific Esterase ◽  
Interleukin 1 Beta ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and cells of the myeloid leukemia cell line HL-60, and that the differentiation is accompanied by increases in expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Because we also showed that TNF-alpha and IL-1 beta can act synergistically to cause monocytoid differentiation of HL-60 cells, we hypothesized that acivicin-induced TNF-alpha and IL-1 beta, in an autocrine manner, caused the differentiation. The purpose of the present study was to determine the causal roles of TNF-alpha and IL-1 beta in the acivicin-induced differentiation of HL-60 cells by the use of dexamethasone (DEX) and pentoxifylline (PTX), two drugs that effectively inhibit expression of TNF-alpha and IL-1 beta. Acivicin caused a monocytoid differentiation of the cells as manifest by diminished cell growth, morphologic maturation of the cells, increased ability to generate hydrogen peroxide in response to acute treatment with phorbol myristate acetate, and increased expression of nonspecific esterase and the surface antigens CD14 and CD11b. Acivicin treatment also caused the cells to have diminished steady-state expression of messenger RNA (mRNA) for c-myc and c-myb, and increased expression of mRNA for TNF-alpha and IL-1 beta. DEX and PTX did not alter cell growth, and did not block the acivicin-induced block in growth. PTX caused a slight increase in nonspecific esterase expression, but DEX had no effect on this, and neither drug diminished the acivicin-induced increase in nonspecific esterase. Although neither drug alone lessened the acivicin enhancement of hydrogen peroxide production, DEX and PTX together reduced this. DEX did not modify the acivicin-induced morphologic maturation of the cells, but PTX alone or PTX with DEX potentiated the acivicin-induced increase in mature cells. Basal CD14 and CD11b expression were slightly reduced by DEX and PTX, but neither drug modified the acivicin-induced increases. DEX and PTX reduced the acivicin-induced increases in TNF-alpha and IL-1 beta mRNA expression, but they had little or no effect on the acivicin-induced decreases in expression of mRNA for c-myc and c-myb. Thus, DEX and PTX effectively block the acivicin-induced expression of TNF-alpha and IL-1 beta, but they have little influence on the acivicin-induced differentiation process.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversible effects of isoproterenol-induced hypertrophy on in situ left ventricular function in rat hearts

2004 ◽  
Vol 287 (1) ◽  
pp. H277-H285 ◽  
Author(s):  
Yutaka Kitagawa ◽  
Daisuke Yamashita ◽  
Haruo Ito ◽  
Miyako Takaki
Keyword(s):  
Cardiac Hypertrophy ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Osmotic Minipump ◽  
Good Index ◽  
Rat Hearts ◽  
Lv Volume ◽  
Work Capability

The aim of the present study was to evaluate specifically left ventricular (LV) function in rat hearts as they transition from the normal to hypertrophic state and back to normal. Either isoproterenol (1.2 and 2.4 mg·kg−1·day−1 for 3 days; Iso group) or vehicle (saline 24 μl·day−1 for 3 days; Sa group) was infused by subcutaneous implantation of an osmotic minipump. After verifying the development of cardiac hypertrophy, we recorded continuous LV pressure-volume (P-V) loops of in situ ejecting hypertrophied rat hearts. The curved LV end-systolic P-V relation (ESPVR) and systolic P-V area (PVA) were obtained from a series of LV P-V loops in the Sa and Iso groups 1 h or 2 days after the removal of the osmotic minipump. PVA at midrange LV volume (PVAmLVV) was taken as a good index for LV work capability ( 13 , 15 , 20 , 21 ). However, in rat hearts during remodeling, whether PVAmLVV is a good index for LV work capability has not been determined yet. In the present study, in contrast to unchanged end-systolic pressure at midrange LV volume, PVAmLVV was significantly decreased by isoproterenol treatment relative to saline; however, these measurements were the same 2 days after pump removal. Simultaneous treatment with a β1-blocker, metoprolol (24 mg·kg−1·day−1), blocked the formation of cardiac hypertrophy and thus PVAmLVV did not decrease. The reversible changes in PVAmLVV reflect precisely the changes in LV work capability in isoproterenol-induced hypertrophied rat hearts mediated by β1-receptors. These results indicate that the present approach may be an appropriate strategy for evaluating the effects of antihypertrophic and antifibrotic modalities.

scholarly journals Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by pentoxifylline and dexamethasone: dissociation of acivicin- induced TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid differentiation

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3337-3343 ◽  
Author(s):  
JB Weinberg ◽  
SN Mason ◽  
TS Wortham
Keyword(s):  
Mrna Expression ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Nonspecific Esterase ◽  
Interleukin 1 Beta ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

Abstract We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and cells of the myeloid leukemia cell line HL-60, and that the differentiation is accompanied by increases in expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Because we also showed that TNF-alpha and IL-1 beta can act synergistically to cause monocytoid differentiation of HL-60 cells, we hypothesized that acivicin-induced TNF-alpha and IL-1 beta, in an autocrine manner, caused the differentiation. The purpose of the present study was to determine the causal roles of TNF-alpha and IL-1 beta in the acivicin-induced differentiation of HL-60 cells by the use of dexamethasone (DEX) and pentoxifylline (PTX), two drugs that effectively inhibit expression of TNF-alpha and IL-1 beta. Acivicin caused a monocytoid differentiation of the cells as manifest by diminished cell growth, morphologic maturation of the cells, increased ability to generate hydrogen peroxide in response to acute treatment with phorbol myristate acetate, and increased expression of nonspecific esterase and the surface antigens CD14 and CD11b. Acivicin treatment also caused the cells to have diminished steady-state expression of messenger RNA (mRNA) for c-myc and c-myb, and increased expression of mRNA for TNF-alpha and IL-1 beta. DEX and PTX did not alter cell growth, and did not block the acivicin-induced block in growth. PTX caused a slight increase in nonspecific esterase expression, but DEX had no effect on this, and neither drug diminished the acivicin-induced increase in nonspecific esterase. Although neither drug alone lessened the acivicin enhancement of hydrogen peroxide production, DEX and PTX together reduced this. DEX did not modify the acivicin-induced morphologic maturation of the cells, but PTX alone or PTX with DEX potentiated the acivicin-induced increase in mature cells. Basal CD14 and CD11b expression were slightly reduced by DEX and PTX, but neither drug modified the acivicin-induced increases. DEX and PTX reduced the acivicin-induced increases in TNF-alpha and IL-1 beta mRNA expression, but they had little or no effect on the acivicin-induced decreases in expression of mRNA for c-myc and c-myb. Thus, DEX and PTX effectively block the acivicin-induced expression of TNF-alpha and IL-1 beta, but they have little influence on the acivicin-induced differentiation process.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Tumor Necrosis Factor-Alpha and Interleukin 6 in Human Periapical Lesions

2007 ◽  
Vol 2007 ◽  
pp. 1-4 ◽  
Author(s):  
Ivana Brekalo Pršo ◽  
Willy Kocjan ◽  
Hrvoje Šimic ◽  
Gordana Brumini ◽  
Sonja Pezelj-Ribaric ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Periapical Lesions ◽  
Factor Alpha ◽  
Necrosis Factor

Aim. The aim of this study was to evaluate the presence of the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in human periapical lesions.Subjects and methods. Samples were obtained from three groups of teeth: symptomatic teeth, asymptomatic lesions, and uninflamed periradicular tissues as a control.Results. TNF-alpha levels were significantly increased in symptomatic lesions compared to control. Group with asymptomatic lesions had significantly higher concentrations compared to control. There were no significant differences in TNF-alpha levels between symptomatic and asymptomatic lesions. In group with symptomatic lesions, IL-6 levels were significantly higher than in group with asymptomatic lesions. The IL-6 levels in symptomatic group also showed significantly higher concentration in comparison with control group. In asymptomatic group, the IL-6 level had significantly higher concentrations compared to control.Conclusion. These results indicate that symptomatic lesions represent an immunologically active stage of disease, and asymptomatic lesions are the point from which the process advances toward healing.

scholarly journals Methylation Status of Promoter Region of Tumor Necrosis Factor Alpha Gene in Subjects with Healthy Gingiva and Chronic Periodontitis - A Pilot Study.

2019 ◽  
Vol 12 (2) ◽  
pp. 639-647 ◽  
Author(s):  
Vamsi Lavu ◽  
V. Vettriselvi ◽  
V. Priyanka ◽  
R. Suresh ◽  
S. K. Balaji
Keyword(s):  
Chronic Periodontitis ◽  
Promoter Region ◽  
Methylation Status ◽  
Tnf Alpha ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Ct Value ◽  
Factor Alpha ◽  
Alpha Gene ◽  
Necrosis Factor

Periodontitis is a multi-factorial disease with bacterial origin. The progression is influenced by systemic disease, smoking, genetic factors. In the recent past epigenetic influences have been indentified on the candidate genes which code for proteins that play a role in the pathogenesis of the periodontal disease. Epigenetic mechanisms involve DNA methylation and histone modification. Till date, there is no existing data associating methylation status of the promoter region (-239, -245) of the TNF alpha gene and chronic periodontitis. The objective of this study was to compare the methylation status of CpG islands in the promoter region of TNF alpha (-239, -245) gene in the peripheral blood among subjects with healthy gingiva and chronic periodontitis. A case control study design involving 50 subjects (25 healthy and 25 subjects with chronic periodontitis) was performed. DNA was isolated from peripheral blood of all the subjects and bisulfate modification with methylation specific polymerase chain reaction (MS-PCR) was performed. The methylation status of the selected region of the Tumor necrosis factor alpha gene for both the test and control groups was evaluated and assessed. The mean Ct value for the methylation of control group was 24.36 and in the periodontitis group the mean Ct value was found to be 28.09. The higher the Ct value, the lower is the amount of methylation observed. The periodontitis group had a higher mean Ct value as compared to the control group; indicating a lower amount of methylation in the promoter region of the periodontitis group as compared to the control group. A lower level of TNF alpha gene promoter (-239,-245) methylation was observed in the periodontitis group as compared to the controls and this observation appears to support a de-methylation of the TNF alpha promoter in the periodontitis subjects. Further studies evaluating the transcript levels of TNF alpha needs to be performed to confirm the observations of this study.

A Brief Regional Ischemic-reperfusion Enhances Propofol-induced Depression in Left Ventricular Function of in situ  Rat Hearts

2004 ◽  
Vol 101 (4) ◽  
pp. 879-887 ◽  
Author(s):  
Naoya Kuzumoto ◽  
Yutaka Kitagawa ◽  
Koichi Uemura ◽  
Takashi Ueyama ◽  
Ken-ichi Yoshida ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Inhibitory Effects ◽  
Ischemic Reperfusion ◽  
Kinase C ◽  
Rat Hearts

Background Propofol is short-acting intravenous general anesthetics that reduces cardiovascular hemodynamics. The effects of propofol on intrinsic myocardial contractility, however, remain debatable. The aim of the current study was to test the hypothesis that inhibitory effects of propofol on left ventricular (LV) contractility and mechanical work capability of in situ ejecting rat hearts are attenuated after a brief regional ischemia and reperfusion. Methods The authors obtained steady-state LV pressure-volume loops and intermittently obtained LV end-systolic pressure-volume relation and evaluated effects of propofol on LV function by end-systolic pressure (ESPmLVV), systolic pressure-volume area (PVAmLVV) at midrange LV volume (mLVV). Results Propofol (5.2 +/- 0.3 approximately 11.1 +/- 3.7 microg.ml) significantly decreased ESP0.08 to 78 +/- 12% approximately 64 +/- 13% of prepropofol and PVA0.08 to 76 +/- 13%approximately 63 +/- 16% of prepropofol in normal hearts, whereas propofol at a lower concentration (4.1 +/- 1.0 microg/ml) did not. Although brief ischemic-reperfusion per se did not affect LV function, propofol after that, even at a lower concentration (4.1 +/- 1.0 microg/ml), significantly decreased ESP0.08 to 70 +/- 27% of prepropofol and PVA0.08 to 68 +/- 33% of prepropofol. Pretreatment with a protein kinase C (PKC) inhibitor, bisindolylmaleimide reduced the propofol (4.1 +/- 1.0 microg/ml)-induced greater decreases in ESP0.08 and PVA0.08 after brief ischemic-reperfusion to 94 +/- 33% and 92 +/- 39% of prepropofol. In the propofol-infused hearts after brief ischemic-reperfusion, protein kinase C-epsilon translocation to the nucleus-myofibril fraction was found. Conclusion In contrast to the study hypothesis, brief ischemic-reperfusion enhanced the inhibitory effects of propofol on LV systolic function; this enhancement is attributable to activation of protein kinase C.

scholarly journals TNF-Alpha in Peripheral Neuropathy Patients with Impaired Glucose Regulation

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Xia Li ◽  
Ju Zhu ◽  
Na Liu ◽  
Jie Liu ◽  
Zhecheng Zhang
Keyword(s):  
Peripheral Neuropathy ◽  
Glucose Regulation ◽  
Tnf Alpha ◽  
Control Group ◽  
Impaired Glucose Regulation ◽  
Healthy Individuals ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor ◽  
Serum Tumor Necrosis

Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF-α and IL-6 in IGR patients were higher than in control group, and serum TNF-α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group (27.7±17.8 versus 13.1±6.7 pg/mL and 18.1±17.7 versus 6.4±3.7 pg/mL, resp., both p<0.05). Multifactors logistic regression analysis showed that TNF-α (OR = 0.893; p=0.009) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF-α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF-α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients.

Impaired cardiac function in rats with healed myocardial infarction: cellular vs. myocardial mechanisms

1994 ◽  
Vol 266 (1) ◽  
pp. C29-C36 ◽  
Author(s):  
J. Y. Cheung ◽  
T. I. Musch ◽  
H. Misawa ◽  
A. Semanchick ◽  
M. Elensky ◽  
...  
Keyword(s):  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Lv Function ◽  
Inotropic Effects ◽  
Cell Shortening ◽  
Subendocardial Ischemia ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Isolated Perfused Rat Hearts

The inotropic responsiveness of isolated perfused rat hearts and single left ventricular (LV) myocytes to extracellular Ca2+ ([Ca2+]o) was examined 3 wk after ligation of left main coronary artery. Myocytes isolated from myocardial infarcted (MI) hearts were 10% longer. At [Ca2+]o of 1.1 mM, cell shortening as well as intracellular Ca2+ concentration dynamics were similar between MI and sham LV myocytes. At [Ca2+]o of 4.9 mM, maximal extent of cell shortening was significantly less in MI myocytes (16 +/- 1 vs. 22 +/- 1%), and peak intracellular Ca2+ concentration was also substantially lower. Thus, under conditions of high [Ca2+]o, decreased sarcolemmal Ca2+ influx and Ca2+ release during excitation-contraction may contribute to systolic dysfunction in MI hearts. Perfused working hearts and isovolumic heart preparations with infarcted LV displayed depressed maximal systolic pressure and decreased sensitivity to the inotropic effects of [Ca2+]o. Our data also indicate that, in addition to possible abnormalities in the contractile response of single myocytes, global factors such as loss of functional myocardium, altered chamber geometry, tissue fibrosis, and/or subendocardial ischemia contributed to depressed LV function in post-MI hearts perfused at physiological [Ca2+]o.

Decrease in left ventricular contractility after tumor necrosis factor-alpha infusion in dogs

1994 ◽  
Vol 76 (3) ◽  
pp. 1060-1067 ◽  
Author(s):  
K. R. Walley ◽  
P. C. Hebert ◽  
Y. Wakai ◽  
P. G. Wilcox ◽  
J. D. Road ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Left Ventricular ◽  
Tnf Alpha ◽  
Ventricular Contractility ◽  
Left Ventricular Contractility ◽  
Necrosis Factor Alpha ◽  
Volume Relationship ◽  
Pressure Volume Relationship ◽  
Factor Alpha ◽  
Necrosis Factor

Whether systolic contractility or diastolic compliance changes soon after tumor necrosis factor-alpha (TNF-alpha) exposure is not known. Accordingly, we measured hemodynamics, left ventricular contractility using the slope of the end-systolic pressure-volume relationship, and diastolic pressure-volume relationships in six control dogs and in six dogs receiving 60 micrograms.kg-1.h-1 i.v. of TNF-alpha. Mean aortic pressure decreased by 22% 1 h after TNF-alpha infusion and remained decreased (P < 0.05). Cardiac output increased by 19% 1 h after TNF-alpha infusion and remained significantly greater than control values (P < 0.05). Left ventricular contractility decreased by 23% (P < 0.05) 1 h after TNF-alpha infusion and decreased by 52% (P < 0.01) 5 h after TNF-alpha infusion. The diastolic pressure-volume relationship did not change in the TNF-alpha group or the control group. Ejection fraction did not change after TNF-alpha infusion despite the decrease in contractility because afterload decreased. We conclude that TNF-alpha is important in causing the hypotensive, hyperdynamic circulation of sepsis. The new finding that left ventricular contractility is decreased shortly after TNF-alpha infusion suggests that TNF-alpha, or another mediator released very soon after TNF-alpha, is an important myocardial depressant factor.

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