title: Na(+)-H+ exchange inhibition attenuates ischemic injury in rat random pattern skin flap: the role of mitochondrial ATP-sensitive potassium channels.
abstract: 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.
authors.affiliation: Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Hamed
authors.initials: H
authors.lastname: Emami
authors.forename: Saman Shafaat
authors.initials: SS
authors.lastname: Talab
authors.forename: Behtash Ghazi
authors.initials: BG
authors.lastname: Nezami
authors.forename: Azadeh
authors.initials: A
authors.lastname: Elmi
authors.forename: Solmaz
authors.initials: S
authors.lastname: Assa
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ostovaneh
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D062109:Dermatologic Surgical Procedures / Q000009:adverse effects*; D003981:Diazoxide / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011183:Postoperative Complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013524:Surgical Flaps / Q000473:pathology*; D014022:Tissue Survival / Q000187:drug effects
chemical_list: D054086:KATP Channels; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D003981:Diazoxide; D005905:Glyburide; C039614:ethylisopropylamiloride