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 resuscitation. In this study, we determined if inhibition of poly(ADP-ribose) synthetase (PARS) activity prevented the development of vascular hyporeactivity in rats following trauma-hemorrhage and resuscitation. Trauma consisted of a laparotomy that was closed and rats were hemorrhaged into a reservoir containing citrate to 40 mm Hg for 90 min. Resuscitation included 2/3 of the shed blood plus 2 1/3 of the shed volume as Ringer's lactate. Sham animals received the laparotomy and were time-matched. Induction of iNOS was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Aortic rings isolated 6 h after the initiation of hemorrhage (4.5 h after resuscitation) showed 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 5x10(-8) M). Addition of the PARS inhibitor, 3-aminobenzamide, at the onset of resuscitation prevented the decrease in response of aortic rings. The addition of the structural analogue, 3-aminobenzoic acid, which does not inhibit PARS, did not prevent the decrease in vascular reactivity. These agents did not alter vascular responses to norepinephrine in sham animals. iNOS induction was not associated with depressed contractile function. These results indicate that decreased vascular reactivity was prevented by inhibition of PARS and that PARS activation was independent of iNOS induction following trauma-hemorrhage and resuscitation.
St John
J
J
Emergency Medicine Research, Carolinas Medical Center, Charlotte, NC 28232-2861, USA.
Barbee
R W
RW
Sonin
N
N
Clemens
M G
MG
Watts
J A
JA
D000818:Animals; D001013:Aorta, Thoracic; D020212:Carotid Artery Injuries / Q000188:drug therapy*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D020198:Intracranial Hemorrhage, Traumatic / Q000188:drug therapy*; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat