title: Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor.
abstract: OBJECTIVE
  In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase.
  
  
  METHODS
  A prospective, controlled, in vivo animal laboratory study.
  
  
  METHODS
  Research laboratory at a university.
  
  
  METHODS
  Male, Wistar rats (8-9 wks old; n = 83).
  
  
  METHODS
  In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer.
  
  
  RESULTS
  LPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration.
  
  
  CONCLUSIONS
  The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Iwase
authors.forename: M
authors.initials: M
authors.lastname: Yokota
authors.forename: K
authors.initials: K
authors.lastname: Kitaichi
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: T
authors.initials: T
authors.lastname: Nagasaka
authors.forename: H
authors.initials: H
authors.lastname: Izawa
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004452:Echocardiography; D004562:Electrocardiography; D019446:Endotoxemia / Q000150:complications* / Q000276:immunology* / Q000378:metabolism; D004837:Epinephrine / Q000097:blood; D006400:Hematocrit; D007546:Isoquinolines / Q000276:immunology / Q000627:therapeutic use*; D007710:Klebsiella Infections / Q000150:complications* / Q000276:immunology* / Q000378:metabolism; D007711:Klebsiella pneumoniae; D008070:Lipopolysaccharides; D008297:Male; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D010975:Platelet Aggregation Inhibitors / Q000276:immunology / Q000627:therapeutic use*; D011446:Prospective Studies; D011726:Pyridinium Compounds / Q000276:immunology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013599:Systole; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000382:microbiology* / Q000517:prevention & control*
chemical_list: D007546:Isoquinolines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D011726:Pyridinium Compounds; D044005:Tetrahydroisoquinolines; C067430:TCV 309; D009638:Norepinephrine; D004837:Epinephrine