title: Leukotriene-mediated coronary vasoconstriction and loss of myocardial contractility evoked by low doses of Escherichia coli hemolysin in perfused rat hearts.
abstract: OBJECTIVE
  hemolysin has been implicated as an important pathogenic factor in extraintestinal infections including sepsis. We investigated the effects of coronary administration of hemolysin on cardiac function in isolated rat hearts perfused at constant flow.
  
  
  METHODS
  Prospective, experimental study.
  
  
  METHODS
  Research laboratory at a university hospital.
  
  
  METHODS
  Isolated hearts from male Wistar rats.
  
  
  METHODS
  Isolated hearts were perfused with purified hemolysin for 60 min.
  
  
  RESULTS
  Low concentrations of the toxin in the perfusate (0.1-0.2 hemolytic units/mL) caused a dose-dependent coronary vasoconstriction with a marked increase in coronary perfusion pressure, which was paralleled by a decrease in left ventricular developed pressure (and the maximum rate of left ventricular pressure increase). Moreover, 0.2 hemolytic units/mL hemolysin evoked ventricular fibrillation within 10 mins of toxin application. These events were accompanied by the liberation of leukotrienes (LTC4, LTD4, LTE4, and LTB4), thromboxane A2, prostaglandin I2, and the cell necrosis markers lactate dehydrogenase and creatine kinase into the recirculating perfusate. The lipoxygenase inhibitor MK-886 fully blocked the toxin-induced coronary vasoconstrictor response and the loss of myocardial contractility and reduced the release of lactate dehydrogenase and creatine kinase. In contrast to this, the cyclooxygenase inhibitor indomethacin was entirely ineffective. In addition, hemolysin elicited an increase in heart weight and left ventricular end-diastolic pressure, the latter again being suppressed by MK-886.
  
  
  CONCLUSIONS
  Low doses of hemolysin cause strong coronary vasoconstriction, linked with loss of myocardial performance, release of cell injury enzymes, and electrical instability, with all events being largely attributable to toxin-elicited leukotriene generation in the coronary vasculature. Bacterial exotoxins such as hemolysin thus may be implicated in the cardiac abnormalities encountered in septic shock.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
authors.forename: Ladislau
authors.initials: L
authors.lastname: Kiss
authors.forename: Pascal
authors.initials: P
authors.lastname: Klingenberger
authors.forename: Martina
authors.initials: M
authors.lastname: Heep
authors.forename: Emmanoyil
authors.initials: E
authors.lastname: Bournelis
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D000818:Animals; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000150:complications*; D005098:Exotoxins / Q000009:adverse effects*; D006333:Heart Failure / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D006460:Hemolysin Proteins / Q000009:adverse effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction; D011446:Prospective Studies; D051381:Rats; D012772:Shock, Septic / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D014661:Vasoconstriction; D018487:Ventricular Dysfunction, Left / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology; D017725:Ventricular Pressure; D002722:Chlorobenzenes
chemical_list: D005098:Exotoxins; D006460:Hemolysin Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes