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Mechanisms responsible for vascular hyporesponsiveness to adrenomedullin after hemorrhage: the central role of adrenomedullin binding protein-1.

AbstractOBJECTIVE:
Irreversible hypovolemia remains a major clinical problem. Preliminary studies indicate that administration of adrenomedullin and adrenomedullin binding protein-1 in combination (AM/AMBP-1) after hemorrhage, improves cardiovascular function despite the increased levels of AM. Our aim was to determine whether vascular responsiveness to AM is reduced after hemorrhage and, if so, to elucidate the possible mechanism responsible for such hyporesponsiveness.
METHODS:
Male rats were bled to and maintained at a mean arterial pressure of 40 mm Hg for 90 minutes. The animals were then resuscitated with 4 times the volume of shed blood with lactated Ringer's solution over 60 minutes. At 1.5 hours postresuscitation, vascular responses to AM and AMBP-1, plasma levels of AM and AMBP-1, AMBP-1 and AM receptor gene expression were measured. In additional animals, AM and AMBP-1 were administered intravenously at 15 minutes after resuscitation over 45 minutes. Serum levels of liver enzymes, lactate, creatinine, TNF-alpha, IL-6, and IL-10 were measured at 1.5 hours postresuscitation.
RESULTS:
AM-induced vascular relaxation decreased significantly after hemorrhage and resuscitation, which was markedly improved by AMBP-1. However, AM receptor gene expression did not change under such conditions. Hemorrhage-induced AM hyporesponsiveness was accompanied by the decreased expression and release of AMBP-1. Moreover, AM/AMBP-1 treatment down-regulated TNF-alpha and IL-6, up-regulated IL-10, and attenuated organ injury.
CONCLUSIONS:
The decreased AMBP-1 levels rather than alterations in AM receptors are responsible for producing AM hyporesponsiveness after hemorrhage. Thus, administration of AMBP-1 in combination with AM can be useful to reduce organ injury after severe hypovolemia.
AuthorsRongqian Wu, Xiaoxuan Cui, Weifeng Dong, Mian Zhou, H Hank Simms, Ping Wang
JournalAnnals of surgery (Ann Surg) Vol. 242 Issue 1 Pg. 115-23 (Jul 2005) ISSN: 0003-4932 [Print] United States
PMID15973109 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Biomarkers
  • CFH protein, human
  • Cytokines
  • Lactates
  • Peptides
  • RNA, Messenger
  • Vasodilator Agents
  • adrenomedullin-binding protein 1, human
  • Adrenomedullin
  • Complement Factor H
  • Creatinine
  • Alanine Transaminase
Topics
  • Adrenomedullin
  • Alanine Transaminase (metabolism)
  • Animals
  • Base Sequence
  • Biomarkers (analysis)
  • Blotting, Western
  • Complement Factor H (pharmacology)
  • Creatinine (metabolism)
  • Cytokines (metabolism)
  • Disease Models, Animal
  • Hemorrhage (blood, physiopathology, therapy)
  • Intestine, Small (blood supply)
  • Lactates (metabolism)
  • Male
  • Molecular Sequence Data
  • Peptides (metabolism, pharmacology)
  • Polymerase Chain Reaction (methods)
  • Probability
  • RNA, Messenger (analysis)
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Resuscitation (methods)
  • Sensitivity and Specificity
  • Shock, Hemorrhagic
  • Vasodilation (drug effects)
  • Vasodilator Agents (metabolism, pharmacology)

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