Endotoxin-induced myocardial dysfunction: Evidence for a role of sphingosine production

被引:22
作者
Favory, R
Lancel, S
Marchetti, P
Mordon, S
Chopin, C
Formstecher, P
Neviere, R
机构
[1] Fac Med Lille, Dept Physiol, F-59045 Lille, France
[2] Fac Med Lille, INSERM U459, F-59045 Lille, France
[3] Univ Lille 2, Fac Med Lille, F-59800 Lille, France
关键词
shock; endotoxin; heart failure; cardiomyocyte; mitochondria; sphingosine;
D O I
10.1097/01.CCM.0000109452.36271.FA
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Objective: To determine whether sphingomyelinase pathway activation would participate in myocardial depression induced by endotoxin. Design: Randomized, controlled trial. Setting: Experimental laboratory. Subjects: Male Sprague-Dawley rats, isolated rat heart, and cardiac myocytes. Interventions: Cardiovascular function was evaluated in rats injected with saline, endotoxin (10 mg/kg, intravenously), and N-oleoylethanolamine (NOE; 10 mg/kg, intravenously). In ex vivo experiments, isolated rat hearts were perfused with endotoxin (5 mug/mL). For pharmacologic intervention, NOE (1 mumol/L) was admixed to the perfusate 20 mins before endotoxin. In in vitro experiments, ventricular myocytes were incubated with sphingosine (20 muM). Myocyte cell shortening and calcium transient were measured. Mitochondrial membrane potential was measured using the cationic dye tetramethylrhodamine methylester fluorescence technique. Measurements and Main Results. Endotoxin treatment at 4 hrs did not alter mean arterial pressure and abdominal blood flow compared with control rats. Left ventricle developed pressure (LVDP) and its first derivatives (i.e., maximal and minimal change in pressure over time [dP/d(max) and dP/d(min)]) were decreased after 4 hrs in endotoxin-treated rats compared with control rats. NOE (10 mg/kg) treatment largely prevented left ventricular systolic function alterations of endotoxin-treated hearts (n = 6 in each group). In isolated rat heart, endotoxin (5 mug/mL) caused increases in tumor necrosis factor-alpha perfusate concentration and delayed depression of LVDP, dP/dt(max), and dP/dt(min) after 60 mins, which was partially abrogated in the presence of the ceramidase inhibitor NOE (1 mumol/L). Sphingosine (20 muM) caused decreases in cell fractional shortening, calcium transient, and mitochondrial membrane potential of cardiac myocytes. Conclusion: These observations suggest that the sphingomyelinase pathway participates in endotoxin-induced myocardial depression.
引用
收藏
页码:495 / 501
页数:7
相关论文
共 38 条
  • [11] NEGATIVE INOTROPIC EFFECTS OF CYTOKINES ON THE HEART MEDIATED BY NITRIC-OXIDE
    FINKEL, MS
    ODDIS, CV
    JACOB, TD
    WATKINS, SC
    HATTLER, BG
    SIMMONS, RL
    [J]. SCIENCE, 1992, 257 (5068) : 387 - 389
  • [12] Sphingosine modulates myocyte electrophysiology, induces negative inotropy, and decreases survival after myocardial ischemia
    Friedrichs, GS
    Swillo, RE
    Jow, B
    Bridal, T
    Numann, R
    Warner, LM
    Killar, LM
    Sidek, K
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2002, 39 (01) : 18 - 28
  • [13] GarciaRuiz C, 1997, J BIOL CHEM, V272, P11369
  • [14] Endotoxin-induced myocardial tumor necrosis factor-α synthesis depresses contractility of isolated rat hearts -: Evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production
    Grandel, U
    Fink, L
    Blum, A
    Heep, M
    Buerke, M
    Kraemer, HJ
    Mayer, K
    Bohle, RM
    Seeger, W
    Grimminger, F
    Sibelius, U
    [J]. CIRCULATION, 2000, 102 (22) : 2758 - 2764
  • [15] Leukocytes and decreased left-ventricular contractility during endotoxemia in rabbits
    Granton, JT
    Goddard, CM
    Allard, MF
    VanEeden, S
    Walley, KR
    [J]. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1997, 155 (06) : 1977 - 1983
  • [16] Cardiac dysfunction in sepsis: new theories and clinical implications
    Grocott-Mason, RM
    Shah, AM
    [J]. INTENSIVE CARE MEDICINE, 1998, 24 (04) : 286 - 295
  • [17] Elucidating the molecular mechanism of the permeability transition pore and its role in reperfusion injury of the heart
    Halestrap, AP
    Kerr, PM
    Javadov, S
    Woodfield, KY
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1998, 1366 (1-2): : 79 - 94
  • [18] Regulation of cardiac myocyte contractile function by inducible nitric oxide synthase (iNOS): Mechanisms of contractile depression by nitric oxide
    Joe, EL
    Schussheim, AE
    Longrois, D
    Maki, T
    Kelly, RA
    Smith, TW
    Balligand, JL
    [J]. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1998, 30 (02) : 303 - 315
  • [19] Nitric oxide and cardiac function
    Kelly, RA
    Balligand, JL
    Smith, TW
    [J]. CIRCULATION RESEARCH, 1996, 79 (03) : 363 - 380
  • [20] The therapeutic potential of modulating the ceramide/sphingomyelin pathway
    Kolesnick, R
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (01) : 3 - 8