Inhibition of poly(adp-ribose) synthetase improves vascular contractile responses following trauma-hemorrhage and resuscitation

Hyporeactivity of vessels to constrictor agents is thought to contribute to cardiovascular decompensation following trauma-hemorrhage and resuscitatio n. In this study, we determined if inhibition of poly(ADP-ribose) synthetas e (PARS) activity prevented the development of vascular hyporeactivity in r ats following trauma-hemorrhage and resuscitation. Trauma consisted of a la parotomy that was closed and rats were hemorrhaged into a reservoir contain ing citrate to 40 mmHg for 90 min. Resuscitation included 2/3 of the shed b lood plus 2 1/3 of the shed volume as Ringer's lactate. Sham animals receiv ed the laparotomy and were time-matched. Induction of iNOS was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Aortic rings isol ated 6 h after the initiation of hemorrhage (4.5 h after resuscitation) sho wed decreased responsiveness to norepinephrine (peak developed tension 0.31 +/- 0.01 g/mg tissue) compared with sham rings (0.43 +/- 0.02 g/mg tissue) , but no change in EC50 for this response (approximately 5 x 10(-8) M). Add ition of the PARS inhibitor, 3-aminobenzamide, at the onset of resuscitatio n prevented the decrease in response of aortic rings. The addition of the s tructural analogue, 3-aminobenzoic acid, which does not inhibit PARS, did n ot prevent the decrease in vascular reactivity. These agents did not alter vascular responses to norepinephrine in sham animals. iNOS induction was no t associated with depressed contractile function. These results indicate th at decreased vascular reactivity was prevented by inhibition of PARS and th at PARS activation was independent of iNOS induction following trauma-hemor rhage and resuscitation.