title: Na+/H+ exchange inhibitor cariporide attenuates skeletal muscle infarction when administered before ischemia or reperfusion.
abstract: Administration of Na(+)/H(+) exchange isoform-1 (NHE-1) inhibitors before ischemia has been shown to attenuate myocardial infarction in several animal models of ischemia-reperfusion injury. However, controversy still exists as to the efficacy of NHE-1 inhibitors in protection of myocardial infarction when administered at the onset of reperfusion. Furthermore, the efficacy of NHE-1 inhibition in protection of skeletal muscle from infarction (necrosis) has not been studied. This information has potential clinical applications in prevention or salvage of skeletal muscle from ischemia-reperfusion injury in elective and trauma reconstructive surgery. The objective of this research project is to test our hypothesis that the NHE-1 inhibitor cariporide is effective in protection of skeletal muscle from infarction when administered at the onset of sustained ischemia or reperfusion and to study the mechanism of action of cariporide. In our studies, we observed that intravenous administration of cariporide 10 min before ischemia (1 or 3 mg/kg) or reperfusion (3 mg/kg) significantly reduced infarction in pig latissimus dorsi muscle flaps compared with the control, when these muscle flaps were subjected to 4 h of ischemia and 48 h of reperfusion (P < 0.05; n = 5 pigs/group). Both preischemic and postischemic cariporide treatment (3 mg/kg) induced a significant decrease in muscle myeloperoxidase activity and mitochondrial-free Ca(2+) content and a significant increase in muscle ATP content within 2 h of reperfusion (P < 0.05; n = 4 pigs/group). Preischemic and postischemic cariporide treatment (3 mg/kg) also significantly inhibited muscle NHE-1 protein expression within 2 h of reperfusion after 4 h of ischemia, compared with the control (P < 0.05; n = 3 pigs/group). These observations support our hypothesis that cariporide attenuates skeletal muscle infarction when administered at the onset of ischemia or reperfusion, and the mechanism involves attenuation of neutrophil accumulation and mitochondrial-free Ca(2+) overload and preservation of ATP synthesis in the early stage of reperfusion.
authors.affiliation: The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: McAllister
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moses
authors.forename: Kunaal
authors.initials: K
authors.lastname: Jindal
authors.forename: Homa
authors.initials: H
authors.lastname: Ashrafpour
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Cahoon
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Neligan
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Forrest
authors.forename: Joan E
authors.initials: JE
authors.lastname: Lipa
authors.forename: Cho Y
authors.initials: CY
authors.lastname: Pang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002369:Castration; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D007238:Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D007275:Injections, Intravenous; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D013524:Surgical Flaps; D013552:Swine; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D000255:Adenosine Triphosphate; D009195:Peroxidase; D002118:Calcium