title: Na(+)/H(+) exchange inhibition-induced cardioprotection in dogs: effects on neutrophils versus cardiomyocytes.
abstract: Numerous studies have examined the effect of Na(+)/H(+) exchanger (NHE) inhibition on the myocardium; however, the effect of NHE-1 inhibition on neutrophil function has not been adequately examined. An in vivo canine model of myocardial ischemia-reperfusion injury in which 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion was used to examine the effect of NHE-1 inhibition on infarct size (IS) and neutrophil function. BIIB-513, a selective inhibitor of NHE-1, was infused before ischemia. IS was expressed as a percentage of area at risk (IS/AAR). NHE-1 inhibition significantly reduced IS/AAR and reduced neutrophil accumulation in the ischemic myocardium. NHE-1 inhibition attenuated both phorbol 12-myristate 13-acetate- and platelet-activating factor-induced neutrophil respiratory burst but not CD18 upregulation. Furthermore, NHE-1 inhibition directly protected cardiomyocytes against metabolic inhibition-induced lactate dehydrogenase release and hypercontracture. This study provides evidence that the cardioprotection induced by NHE-1 inhibition is likely due to specific protection of cardiomyocytes and attenuation of neutrophil activity.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Gumina
authors.forename: J
authors.initials: J
authors.lastname: Auchampach
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Buerger
authors.forename: C
authors.initials: C
authors.lastname: Eickmeier
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.forename: J
authors.initials: J
authors.lastname: Daemmgen
authors.forename: G J
authors.initials: GJ
authors.lastname: Gross
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D003097:Collateral Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005740:Gases / Q000097:blood; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008698:Mesylates / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
chemical_list: D018821:CD18 Antigens; D005740:Gases; D008698:Mesylates; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D009195:Peroxidase; C402725:BIIB 513