Adrenomedullin is increased in the portal circulation during chronic sepsis in rats.
BACKGROUND
A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis.


METHODS
Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA.


RESULTS
Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated.


CONCLUSIONS
These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.
Matheson
Paul J
PJ
Department of Surgery, University of Louisville, 800 Zorn Avenue, Research Bldg. 19, Louisville, KY 40206, USA. pjmath01@athena.louisville.edu
Mays
Michael P
MP
Hurt
Ryan T
RT
Harris
Patrick D
PD
Garrison
R Neal
RN
D000208:Acute Disease; D053607:Adrenomedullin; D000818:Animals; D016470:Bacteremia / Q000097:blood; D001442:Bacteroides Infections / Q000097:blood; D001441:Bacteroides fragilis; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000097:blood; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood / Q000209:etiology; D010455:Peptides / Q000097:blood*; D011168:Portal System / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood*; D013997:Time Factors; D014665:Vasodilator Agents / Q000097:blood*
D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin