Role of platelet-activating factor in hepatocellular Ca2+ alterations during hemorrhagic shock.
A role of the potent proinflammatory Ca2+ agonist platelet-activating factor (PAF) on hepatocellular Ca2+ homeostasis and oxidant injury was investigated, since Ca2+ dysregulation has been demonstrated as a pivotal pathomechanism causing hepatic dysfunction during hemorrhagic or septic shock. In anesthetized male Sprague-Dawley rats, blood was withdrawn to a mean arterial blood pressure of 40 mm Hg for 60 min. Rats were resuscitated with 60% of shed blood and threefold the shed blood volume of lactated Ringers' (shock group). After 60 min of resuscitation, hepatocytes were isolated by portal collagenase perfusion. Hepatocellular Ca2+ uptake (Caup2+), initial rate of Ca2+ influx (Cain2+), and membrane Ca2+ flux (Caflux2+) were determined using 45Ca2+ incubation techniques. Hepatocyte oxidant injury was fluorometrically determined by thiobarbituric acid reactive substances. Caup2+ (3.37 +/- 0.15 vs. 2. 53 +/- 0.08 nmole Ca2+/mg protein), Cain2+ (0.42 +/- 0.1 vs. 0.27 +/- 0.02 nmole Ca2+/mg protein/min), and Caflux2+ (31.3 +/- 4.3 vs. 16.9 +/- 2.4 pmole Ca2+/mg/min) significantly increased in the untreated shock group compared to untreated sham-operated rats (P < 0.05). The specific PAF receptor antagonist BN52021 given 5 min before (5 mg/kg b.w.) and continuously during resuscitation (5 mg/kg/hr) significantly reduced Caup2+ in the shock group (2.73 +/- 0.2; P < 0.01) and prevented hepatocyte lipid peroxidation (shock: 91.9 +/- 1; shockBN52021: 66.7 +/- 2 nmole/mg wet weight; P < 0.01). These data suggest that platelet-activating factor plays a pivotal role in promoting hepatocyte Ca2+ overload during hemorrhagic shock by releasing Ca2+ agonistic mediators and inducing oxidative membrane alterations both of which are capable of enhancing cellular Ca2+ influx.
Silomon
M
M
Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, Homburg, 66421, Germany.
Pizanis
A
A
Larsen
R
R
Rose
S
S
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism* / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004224:Diterpenes; D005609:Free Radicals / Q000494:pharmacology; D046934:Ginkgolides; D006439:Hemodynamics; D006706:Homeostasis; D007783:Lactones / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D010084:Oxidation-Reduction; D010972:Platelet Activating Factor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D013997:Time Factors
D004224:Diterpenes; D005609:Free Radicals; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017392:Thiobarbituric Acid Reactive Substances; C039351:platelet activating factor receptor; C045856:ginkgolide B; D002118:Calcium