Candesartan improves survival following severe hypovolemia in pigs; a role for the angiotensin II type 2 receptor?
OBJECTIVE
To investigate the involvement of intestinal angiotensin II type 2 receptors in the outcome of acute severe hypovolemia as well as systemic and regional mesenteric hemodynamics and intestinal mucosal functions in anesthetized pigs.


METHODS
Prospective, interventional animal study in a university research laboratory.


METHODS
53 landrace pigs, 28-35 kg.


METHODS
30+30% or 20+20% hemorrhage of estimated total blood volume followed by retransfusion performed in untreated controls, in animals treated with the angiotensin II type 1 receptor blocker candesartan or with a combination of candesartan and the angiotensin II type 2 receptor blocker PD123319.


RESULTS
Following 30+30% hemorrhage the candesartan-treated animals attained a significantly higher survival rate than controls and animals treated with PD123319 in combination with candesartan. Less pronounced hemorrhage (20+20%) resulted in no mortality and functional variables were assessed. A significantly higher output of jejunal intraluminal nitric oxide occurred during hypovolemia in the candesartan treated group than in controls and animals that received PD123319 in combination with candesartan. Jejunal transmucosal potential difference was significantly better preserved after retransfusion in candesartan-treated animals than in controls. Expression of angiotensin II type 2 receptors in intestinal tissue was significantly higher in animals surviving the 30+30% hemorrhage than in nonsurvivors.


CONCLUSIONS
Lethal circulatory failure is possibly influenced by use of angiotensin receptor ligands, and activation of intestinal angiotensin II type 2 receptors may play a significant role in improving the outcome of severe hypovolemia.
Laesser
Mats
M
Department of Gastrosurgical Research, Institute of Surgical Sciences, Sahlgrenska Academy, University of Gothenburg, Box 75038, 40036 Gothenburg, Sweden.
Spak
Emma
E
Ewert
Sara
S
Aneman
Anders
A
Fandriks
Lars
L
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D020896:Hypovolemia / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D011446:Prospective Studies; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D015996:Survival Rate; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C081643:candesartan