Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation

Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme po ly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and l eads to vascular dysfunction. We hypothesized that PARS inhibition would at tenuate injury to mechanisms of pulmonary vasorelaxation in acute lung inju ry. The purpose of this study was to determine the effect of in vivo PARS i nhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats rece ived intraperitoneal saline or Etx (Salmonella typhimurium; 20 mg/kg) and o ne of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamid e (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothel ium-dependent (response to ACh and calcium ionophore) and -independent (sod ium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Et x-induced impairment of endothelium-dependent and -independent pulmonary va sorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung m yeloperoxidase activity and edema. Lung ATP decreased after Etx but was mai ntained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefol d 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 inhib it PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injur y.