Adrenomedullin and adrenomedullin binding protein-1 prevent metabolic acidosis after uncontrolled hemorrhage in rats.
OBJECTIVE
Management of trauma victims with uncontrolled hemorrhage remains a major problem in combat casualty care at the far-forward battlefield setting. The neuroendocrine response to hemorrhage is to maintain perfusion to the heart and brain, often at the expense of other organ systems. Decreased organ perfusion after hemorrhagic shock is associated with metabolic acidosis, in which the up-regulated endothelin-1 plays an important role. We have recently shown that vascular responsiveness to adrenomedullin (AM), a newly discovered vasodilator peptide, is depressed after hemorrhage and resuscitation. Down-regulation of AM binding protein (AMBP-1) appears to be responsible for this hyporesponsiveness. We therefore hypothesized that administration of AM/AMBP-1 would prevent metabolic acidosis after uncontrolled hemorrhage via down-regulation of endothelin-1.


METHODS
Prospective, controlled, and randomized animal study.


METHODS
A research institute laboratory.


METHODS
Male Sprague-Dawley rats (275-325 g).


METHODS
A rat model of uncontrolled hemorrhage with an extremely low volume of fluid resuscitation was used to mimic the combat situation.


RESULTS
Both lumbar veins of male adult rats were isolated and severed at the junction to the vena cava. The abdomen was kept open but covered with a saline wet gauze for 45 mins and then closed in layers. The animals received 1 mL of normal saline (vehicle) with or without AM (12 microg/kg of body weight) and AMBP-1 (40 microg/kg of body weight) over 45 mins. Various variables were measured at 4 hrs after resuscitation. The bleed-out volumes in the vehicle group and the AM/ AMBP-1 treatment group were 6.78 +/- 0.19 and 6.81 +/- 0.25 mL/rat, respectively. The results indicate that AM/AMBP-1 administration prevented metabolic acidosis, mitigated organ injury, down-regulated preproendothelin-1 gene expression, and decreased plasma levels of endothelin-1 after hemorrhage.


CONCLUSIONS
AM/AMBP-1 may provide a novel approach for the treatment of uncontrolled hemorrhage. The beneficial effect of AM/AMBP-1 is associated with down-regulation of endothelin-1.
Wu
Rongqian
R
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, NY, USA.
Dong
Weifeng
W
Zhou
Mian
M
Simms
H Hank
HH
Marini
Corrado P
CP
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D000138:Acidosis / Q000503:physiopathology / Q000517:prevention & control*; D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D017242:Complement Factor H / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006400:Hematocrit; D008297:Male; D010100:Oxygen / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D019332:Endothelin-1; D012333:RNA, Messenger; D014665:Vasodilator Agents; C481978:adrenomedullin-binding protein 1, rat; D053607:Adrenomedullin; D017242:Complement Factor H; D010100:Oxygen