Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation.
Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats received intraperitoneal saline or Etx (Salmonella typhimurium; 20 mg/kg) and one of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamide (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothelium-dependent (response to ACh and calcium ionophore) and -independent (sodium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Etx-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung myeloperoxidase activity and edema. Lung ATP decreased after Etx but was maintained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefold after Etx, which 3-AB and Nic prevented. The beneficial effects were not observed with benzoic acid, a structural analog of 3-AB that does not inhibit PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injury.
Pulido
E J
EJ
Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital, Denver 80262, Colorado.
Shames
B D
BD
Selzman
C H
CH
Barton
H A
HA
Banerjee
A
A
Bensard
D D
DD
McIntyre
R C
RC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D006152:Cyclic GMP / Q000502:physiology; D019446:Endotoxemia / Q000201:enzymology / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009536:Niacinamide / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011652:Pulmonary Circulation / Q000187:drug effects*; D011654:Pulmonary Edema / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001549:Benzamides; D004731:Endotoxins; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D009195:Peroxidase; D006152:Cyclic GMP