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Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by
G M Wray1, C J Hinds, C Thiemermann
1The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, United Kingdom.
Abstract:
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.
Insights
Poly(ADP-ribose) synthetase (PARS) inhibition did not prevent circulatory failure or organ damage in endotoxin-induced shock. PARS activation is unlikely to contribute to the pathology of endotoxic shock in rats.
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Poly(ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by DNA damage.
- PARS activation can lead to cell death and may contribute to endotoxin-induced shock.
- Nitric oxide (NO), peroxynitrite, and free radicals activate PARS.
Purpose of the Study:
- To investigate the effects of PARS inhibitors on endotoxin-induced circulatory failure and organ dysfunction in rats.
- To determine if PARS activation contributes to the pathophysiology of endotoxic shock.
Main Methods:
- Rats were administered lipopolysaccharide (LPS) to induce endotoxic shock.
- Various PARS inhibitors (3-aminobenzamide, nicotinamide, 1,5-dihydroxyisoquinoline) were administered.
- Circulatory failure, renal dysfunction, liver injury, pancreatic injury, plasma lactate, and NO production were measured.
Main Results:
- LPS administration caused circulatory failure, renal dysfunction, liver and pancreatic injury, elevated lactate, and NO overproduction.
- None of the PARS inhibitors tested ameliorated circulatory failure, renal dysfunction, lactate levels, or NO overproduction.
- 1,5-dihydroxyisoquinoline showed some benefit for liver and pancreatic injury markers, but this was attributed to its vehicle (DMSO), a free radical scavenger.
Conclusions:
- PARS activation does not contribute to circulatory failure, renal dysfunction, lactic acidosis, or NO overproduction in endotoxic shock.
- PARS is unlikely to play a significant role in the liver injury/dysfunction observed in rat endotoxic shock.
- The findings suggest that PARS inhibition is not a viable therapeutic strategy for endotoxic shock.