Effects of 5-aminoisoquinolinone, a water-soluble, potent inhibitor of the activity of poly (ADP-ribose) polymerase on the organ injury and dysfunction caused by haemorrhagic shock.
Poly (ADP-ribose) synthetase (PARP) is a nuclear enzyme activated by strand breaks in DNA, which are caused inter alia by reactive oxygen species (ROS). Here we report on (i) a new synthesis of a water-soluble and potent PARP inhibitor, 5-aminoisoquinolinone (5-AIQ) and (ii) investigate the effects of 5-AIQ on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. Exposure of human cardiac myoblasts (Girardi cells) to hydrogen peroxide (H(2)O(2), 3 mM for 1 h, n=9) caused a substantial increase in PARP activity. Pre-treatment of these cells with 5-AIQ (1 microM - 1 mM, 10 min prior to H(2)O(2)) caused a concentration-dependent inhibition of PARP activity (IC(50): approximately 0.01 mM, n=6). Haemorrhage and resuscitation resulted (within 4 h after resuscitation) in a delayed fall in blood pressure (circulatory failure) as well as in rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl-transferase (gamma-GT) (liver injury and dysfunction), (iii) lipase (pancreatic injury) and (iv) creatine kinase (CK) (neuromuscular injury) (n=10). Administration (5 min prior to resuscitation of 5-AIQ) (0.03 mg kg(-1) i.v., n=8, or 0.3 mg kg(-1) i.v., n=10) reduced (in a dose-related fashion) the multiple organ injury and dysfunction, but did not affect the circulatory failure, associated with haemorrhagic shock. Thus, 5-AIQ abolishes the multiple organ injury caused by severe haemorrhage and resuscitation.
McDonald
M C
MC
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ.
Mota-Filipe
H
H
Wright
J A
JA
Abdelrahman
M
M
Threadgill
M D
MD
Thompson
A S
AS
Thiemermann
C
C
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003402:Creatine Kinase / Q000097:blood / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008049:Lipase / Q000097:blood / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009102:Multiple Organ Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000150:complications*; D012995:Solubility; D014508:Urea / Q000097:blood; D014867:Water; D005723:gamma-Glutamyltransferase / Q000097:blood / Q000187:drug effects
C411425:5-aminoisoquinolinone; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014867:Water; D014508:Urea; D003404:Creatinine; D006861:Hydrogen Peroxide; D005723:gamma-Glutamyltransferase; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D008049:Lipase