Activation of poly(ADP-ribose) polymerase in severe hemorrhagic shock and resuscitation.
This study examines activation of poly(ADP-ribose) polymerase (PARP) in the ileum during hemorrhage and resuscitation and determines if inhibition of PARP reduces organ dysfunction and metabolic acidosis. Awake, nonheparinized rats were hemorrhaged (40 mmHg, 60 min). Resuscitation used Ringer's solution (2 1/3 x shed volume) and packed red blood cells (2/3 shed volume). Ileal PARP activity was elevated at the end of hemorrhage (3.6-fold) and 10 min of resuscitation (5-fold). The subsequent decline in PARP activity observed after 60 min of resuscitation was not due to cleavage by caspase-3. Ileum permeability increased 10-fold and circulating liver enzymes increased 4- to 6-fold following 60 min of resuscitation in animals pretreated with 3-aminobenzoic acid, a structural analog that does not inhibit PARP. Pretreatment with 3-aminobenzamide (3-AB), a PARP inhibitor, reduced these changes, whereas posttreatment with a bolus of 3-AB was ineffective. Metabolic acidosis, accumulation of lactate, and base deficit was reduced by pretreatment with 3-AB. PARP is activated in the ileum by hemorrhage and by resuscitation. Activation of PARP contributes to organ dysfunction in the ileum and liver and appears to be central to the development of metabolic acidosis.
Watts
J A
JA
Emergency Medicine Research, Carolinas Medical Center, Charlotte, North Carolina 28232-2861, USA. jwatts@carolinas.org
Grattan
R M
RM
Whitlow
B S
BS
Kline
J A
JA
D000138:Acidosis / Q000209:etiology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007082:Ileum / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology; D010539:Permeability; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology
D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases