N-acetylcysteine administration improves platelet aggregation in hypoxia-reoxygenation injury.
Platelet activation and dysfunction occurs upon hypoxia and reoxygenation and is associated with oxygen free radical generation and matrix metalloproteinase (MMP) -2 and -9 activation. The effect of NAC on platelet function in newborn piglets after asphyxia was studied along with plasma MMP-2 and MMP-9 activities. Piglets (1-4 day, 1.4-2.2 kg) were acutely instrumented for the induction of normocapnic hypoxia (10-15% O2) for 2hr followed by reoxygenation for 1hr with 100% O2 and then 3hr with 21% O2. Animals were randomized to 3 groups (n = 6 each); sham, control and treatment with NAC upon reoxygenation (150 mg/kg i.v. bolus and 100 mg/kg/hr i.v. infusion). Platelet count and collagen (2, 5 and 10 microg/mL)-stimulated whole blood aggregation were studied at baseline and after 4hr reoxygenation. Plasma MMP -2 and -9 activities were analyzed by gelatin zymography. Piglets had severe hypoxia (PaO2 32 +/- 2 vs. 65 +/- 2 mmHg sham; p < 0.05) and metabolic acidosis (pH 6.96 +/- 0.04 vs. 7.33 +/- 0.01 sham; p < 0.05). At 4hr of reoxygenation, platelet counts decreased similarly in all experimental groups, and no animal had a platelet count < 100 x 10(9)/L. Platelet aggregation was significantly reduced with a rightward shift of concentration-response curve. NAC treatment improved platelet aggregatory function at 4hr of reoxygenation (p < 0.05). Plasma MMP-9, but not MMP-2, activities were increased with NAC treatment (147 +/- 19 vs. 51 +/- 20 and 42 +/- 11 AU of control and sham, respectively, p < 0.001). In a newborn piglet model of asphyxia and reoxygenation, NAC treatment effectively improves platelet aggregation when given upon resuscitation.
Chan
Emily
E
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Obaid
Laila
L
Johnson
Scott T
ST
Bigam
David L
DL
Cheung
Po-Yin
PY
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000860:Hypoxia / Q000097:blood*; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D010100:Oxygen / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects*; D010976:Platelet Count; D013552:Swine
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010100:Oxygen; D000111:Acetylcysteine