Angiotensin II type 2 receptor decreases ischemia reperfusion induced fluid leak.
BACKGROUND
Intravascular volume loss from ischemia-reperfusion (IR) injury is a major clinical concern. We hypothesize that angiotensin II decreases IR-mediated microvascular fluid leak via the angiotensin II type 2 receptor in a cAMP dependent manner. We therefore sought to determine hydraulic permeability after IR of venules treated with 1) angiotensin II, 2) angiotensin II and cAMP synthesis inhibitor, and 3) angiotensin II and an angiotensin II type 2 receptor antagonist.


METHODS
Rat mesenteric post-capillary venules were micro-cannulated to measure hydraulic permeability (L(p)). IR was achieved by placing animals in a 5% oxygen environment and preventing venular flow, after which blood flow was allowed to resume. L(p) was measured after IR and treatment with 1) angiotensin II (20 nm), 2) angiotensin II (20 nm) + cAMP synthesis inhibitor (DDA,10uM), and 3) angiotensin II (20 nm) + type 2 receptor antagonist (PD-123319, 300 mum) (n=6 in each group).


RESULTS
Compared with the seven-fold increase in L(p) because of IR alone: 1) angiotensin II attenuated the seven-fold increase by 50% (P<0.005), 2) cAMP inhibition did not change the effect of angiotensin II on leak, and the type 2 receptor antagonist completely blocked the effects of angiotensin II on IR mediated leak.


CONCLUSIONS
Treatment with angiotensin II attenuated increases in hydraulic permeability because of IR by 50%. Inhibition of cAMP synthesis did not change the effect of angiotensin II on IR mediated leak, and angiotensin II type 2 receptor inhibition completely blocked the effects of angiotensin II. These results indicate that angiotensin II decreases IR induced leak via the angiotensin II type 2 receptor in a cAMP independent manner. A better understanding of mediators that reduce intravascular fluid loss from IR-induced microvascular dysfunction may help clinicians treat uncontrolled fluid extravasation that occurs during shock and sepsis.
Ramirez
René
R
Department of Surgery, UCSF-East Bay, Alameda County Medical Center, Alameda, California, USA.
Chong
Terry
T
Curran
Brian
B
Sadjadi
Javid
J
Victorino
Gregory P
GP
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001826:Body Fluids / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D016048:Dideoxyadenosine / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology; D014699:Venules / Q000378:metabolism*
D057912:Angiotensin II Type 2 Receptor Blockers; D000963:Antimetabolites; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D016048:Dideoxyadenosine; D000242:Cyclic AMP; D010100:Oxygen