Necrosis of distal portion of skin flaps due to
ischemia still remains a problem in plastic surgery. Following
ischemia, a cascade of deleterious events including over-activity of
Na(+)-H(+) Exchanger (NHE) takes place. In present study we evaluated the effect of the potent NHE inhibitor, 5-(N-ethyl-N-isopropyl)
amiloride (
EIPA) on ischemic tissue injury in a skin flap model, and investigated the role of mitochondrial
ATP-sensitive K(+) channels (K(
ATP)) in this phenomenon. Seventy-eight rats were randomly divided into thirteen treatment groups (6 rats each). Four groups received different doses of
EIPA in the flap.
EIPA/GLY group received an effective dose of a K(
ATP) channel blocker,
glibenclamide (GLY, 0.3mg/kg) intraperitoneally (i.
p.) 30 min before raising the flap, and a local effective dose of
EIPA (0.1mM) immediately after raising the flap.
EIPA/
diazoxide group (
EIPA/
DIA) received a sub-effective dose of
diazoxide (7.5mg/kg i.
p.) 30 min before raising the flap and a local sub-effective dose of
EIPA (0.075 mM).
EIPA 0.1 and 0.2mM significantly increased flap survival area compared to control group (56.01 ± 6.1%, P<0.001). The protective effect of
EIPA (0.1mM) was abolished by administration of
glibenclamide (0.3mg/kg i.p.). Co-administration of a sub-effective dose of
EIPA (0.075 mM), with a sub-effective dose of
diazoxide (7.5mg/kg i.p.) significantly improved flap survival (P<0.05). We demonstrated that the NHE inhibitor,
EIPA can increase random pattern skin flap survival. Administration of
diazoxide potentiates this effect, while
glibenclamide abolishes that, implicating that the protective effect of
EIPA is mediated through mitochondrial-K(
ATP) channels.