A novel approach to maintaining cardiovascular stability after hemorrhagic shock: beneficial effects of adrenomedullin and its binding protein.
BACKGROUND
Vascular responsiveness to adrenomedullin (AM), a recently discovered vasodilator peptide, is depressed after hemorrhage and resuscitation. Downregulation of AM binding protein-1 (ie, AMBP-1) appears to be responsible for this hyporesponsiveness. Therefore, we hypothesize that administration of AM/AMBP-1 improves cardiovascular responses after hemorrhagic shock and resuscitation.


METHODS
Male rats were bled to and maintained at a mean blood pressure of 40 mm Hg for 90 minutes. The animals were then resuscitated with 4 times the volume of shed blood with Ringer's lactate over 60 minutes. At 15 minutes after the beginning of resuscitation in hemorrhaged animals, AM alone, AMBP-1 alone, AM in combination with AMBP-1, or vehicle (phosphate-buffered saline solution) was administered intravenously over 45 minutes. At 4-hour postresuscitation, in vivo left ventricular contractility parameters, maximal rates of ventricular pressure increase (+dP/dt max ) and decrease (-dP/dt max ), were determined. Cardiac output and organ blood flow were measured with the use of radioactive microspheres. In an additional group of animals, cardiac tumor necrosis factor-alpha (TNF-alpha) levels were measured by an enzyme-linked immunosorbent assay.


RESULTS
Four hours after resuscitation, +dP/dt max , -dP/dt max , cardiac output, and organ blood flow in the liver, small intestine, and kidneys were decreased while treatment with AM/AMBP-1 increased these parameters ( P < .05). Moreover, cardiac TNF-alpha levels were elevated at 4 hours after hemorrhage and resuscitation, while AM/AMBP-1 treatment reduced them to sham levels ( P < .05).


CONCLUSIONS
Administration of AM/AMBP-1 appears to be a useful approach for restoring and maintaining cardiovascular stability after severe hemorrhagic shock and crystalloid resuscitation.
Wu
Rongqian
R
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, 350 Community Drive, Manhasset, NY 11030, USA.
Dong
Weifeng
W
Zhou
Mian
M
Cui
Xiaoxuan
X
Simms
H Hank
HH
Wang
Ping
P
D053607:Adrenomedullin; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D017242:Complement Factor H / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D053607:Adrenomedullin; D017242:Complement Factor H; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C493495:CFH protein, human