Tyrphostin reduces the organ injury in haemorrhagic shock: role of inducible nitric oxide synthase.
We investigate the effects of the tyrosine kinase inhibitor, tyrphostin AG126 on the organ injury and dysfunction (kidney, liver, pancreas, muscle and or brain) associated with haemorrhagic shock in the anaesthetised rat. Haemorrhage (sufficient to lower mean arterial blood pressure to 45 mmHg for 90 min) and subsequent resuscitation with the shed blood resulted (within 4 h after resuscitation) in expression of inducible nitric oxide synthase inhibitor (iNOS), positive staining for nitrotyrosine (liver), renal, liver and pancreatic injury, and injury to the muscle and brain. Pre-treatment (30 min prior to the onset of haemorrhage) with the tyrosine kinase inhibitor tyrphostin AG126 reduced the iNOS expression, nitrotyrosine formation, hepatic, brain or muscular injury, and to a lesser extent, the renal injury caused by haemorrhage and resuscitation. Selective inhibition of iNOS activity with N-(3-(aminomethyl)benzyl) acetamidine (1400 W, 10 mg kg(-1) i.v., 5 min prior to the onset of resuscitation), also attenuated nitrotyrosine formation, renal dysfunction, liver injury and brain or muscular injury associated with haemorrhagic shock. The expression of iNOS protein was unaffected by 1400 W. We propose that the activation of tyrosine kinases and the induction of iNOS contribute to the multiple organ injury caused by severe haemorrhage and resuscitation.
McDonald
Michelle
M
The Royal London School of Medicine and Dentistry, University of London, EC1M 6BQ London, UK.
Abdelrahman
Maha
M
Cuzzocrea
Salvatore
S
Thiemermann
Christoph
C
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009102:Multiple Organ Failure / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000188:drug therapy; D020032:Tyrphostins / Q000494:pharmacology / Q000627:therapeutic use*
D000578:Amidines; D001596:Benzylamines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D020032:Tyrphostins; C482020:tyrphostin AG 126; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D003402:Creatine Kinase