Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin.
The nuclear enzyme poly(ADP-ribose) synthetase (PARS) is activated by DNA strand breakage, caused, for example by nitric oxide (NO), peroxynitrite, or oxygen-derived free radicals. Activation of PARS can cause intracellular energy depletion and cell death in vitro and may play a role in the circulatory and organ failure caused by endotoxin (LPS). Here we investigate the effects of various chemically distinct inhibitors of PARS activity (3-aminobenzamide, nicotinamide, 1,5-dihydroxyisoquinoline) on circulatory failure and organ dysfunction caused by LPS in the rat. Administration of endotoxin caused circulatory failure, acute renal dysfunction, hepatocellular injury and dysfunction, pancreatic injury, elevation of plasma lactate levels, and overproduction of NO. None of the PARS inhibitors used reduced the circulatory failure, the renal dysfunction, rise in lactate, or the overproduction of NO caused by LPS. Although 1,5-dihydroxyisoquinoline (ISO) attenuated the rises in the serum levels of bilirubin, alanine aminotransferase (ALT) (indicators of liver injury/dysfunction), and lipase (indicator of pancreatic injury); a similar effect was also observed with the vehicle for ISO, dimethyl sulfoxide (DMSO), which is a well known scavenger of hydroxyl radicals. Thus, the beneficial effects of ISO are unlikely to be due to inhibition of PARS activity, but may be due to the scavenging of free radicals by its vehicle DMSO. Activation of PARS does not contribute to the circulatory failure, renal dysfunction, lactic acidosis, or the overproduction of NO and is unlikely to contribute to the liver injury/dysfunction caused by endotoxic shock in the rat.
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, United Kingdom.
G M
GM
Wray
C J
CJ
Hinds
C
C
Thiemermann
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019446:Endotoxemia / Q000150:complications* / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000188:drug therapy*; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009102:Multiple Organ Failure / Q000188:drug therapy*; D009536:Niacinamide / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010179:Pancreas / Q000187:drug effects / Q000503:physiopathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D004113:Succimer / Q000494:pharmacology
D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009566:Nitrates; D009573:Nitrites; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D019344:Lactic Acid; C095653:1,5-dihydroxyisoquinoline; C025160:3-aminobenzamide; D004113:Succimer