title: Disruption of chronic cariporide treatment abrogates myocardial ion homeostasis during acute ischemia reperfusion.
abstract: Cariporide, an Na/H exchanger inhibitor, is a drug with cardioprotective properties. However, chronic treatment with cariporide may modify the protein phenotype of the cardiomyocytes. Disruption of the equilibrium between a cariporide-modified phenotype and the supply of cariporide could be deleterious. The aim of this study was to test the effects of this equilibrium rupture (EqR) on cardiac function at baseline and acute ischemia reperfusion. Rats were chronically treated with cariporide (2.5 mg·kg·d) or with placebo for 21 days, after which isolated Langendorff-mode heart perfusion experiments utilized cariporide-free buffer. During this type of perfusion, the drug is rapidly cleared from the cellular environment. After 30 minutes of stabilization, the hearts were subjected to global zero-flow ischemia (25 minutes) followed by reperfusion (45 minutes). Measures of mechanical function, oxygen consumption, lactate plus pyruvate, CO2 and proton release into the coronary effluent were determined. The gene and protein expression of proton extruders was also evaluated. Chronic cariporide administration followed by EqR reduced the expression of the Na/H exchanger, increased the expression of the HCO3 or Na exchanger, decreased monocarboxylate/H carrier expression, reduced the lactate plus pyruvate release but did not change the glucose oxidation rate and mechanical function compared with baseline conditions. The resulting low glycolytic rate was associated with a stronger contracture during ischemia. During reperfusion, the early release of acidic forms was higher and redirected toward the use of the Na/H and HCO3 /Na exchangers to the detriment of the safe monocarboxylate/H carrier. Both phenomena were assumed to increase the Na uptake and activate the Na/Ca exchanger, resulting in Na and Ca overload and further cellular damage. This explains the impaired recovery of the contractile function observed in the EqR group during reperfusion. In conclusion, although cariporide is usually cardioprotective, a disruption of its chronic treatment followed by an ischemia/reperfusion event can become deleterious.
authors.affiliation: Laboratoire de Bioénergétique Fondamentale et Appliquée, INSERM U1055, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bourahla
authors.forename: Herve
authors.initials: H
authors.lastname: Dubouchaud
authors.forename: Evangelia
authors.initials: E
authors.lastname: Mourmoura
authors.forename: Damien
authors.initials: D
authors.lastname: Vitiello
authors.forename: Patrice
authors.initials: P
authors.lastname: Faure
authors.forename: Carole
authors.initials: C
authors.lastname: Migné
authors.forename: Estelle
authors.initials: E
authors.lastname: Pujos-Guillot
authors.forename: Melanie
authors.initials: M
authors.lastname: Richardson
authors.forename: Luc
authors.initials: L
authors.lastname: Demaison
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000517:prevention & control*; D001774:Blood Chemical Analysis; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006334:Heart Function Tests; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D027982:Sodium-Bicarbonate Symporters / Q000096:biosynthesis / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000235:genetics; D013450:Sulfones / Q000378:metabolism / Q000494:pharmacology*; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D006146:Guanidines; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C422004:Slc4a4 protein, rat; C093373:cariporide