title: Amino acid transamination is crucial for ischaemic cardioprotection in normal and preconditioned isolated rat hearts--focus on L-glutamate.
abstract: We have found that cardioprotection by l-glutamate mimics protection by classical ischaemic preconditioning (IPC). We investigated whether the effect of IPC involves amino acid transamination and whether IPC modulates myocardial glutamate metabolism. In a glucose-perfused, isolated rat heart model subjected to 40 min global no-flow ischaemia and 120 min reperfusion, the effects of IPC (2 cycles of 5 min ischaemia and 5 min reperfusion) and continuous glutamate (20 mm) administration during reperfusion on infarct size and haemodynamic recovery were studied. The effect of inhibiting amino acid transamination was evaluated by adding the amino acid transaminase inhibitor amino-oxyacetate (AOA; 0.025 mm) during reperfusion. Changes in coronary effluent, interstitial (microdialysis) and intracellular glutamate ([GLUT](i)) concentrations were measured. Ischaemic preconditioning and postischaemic glutamate administration reduced infarct size to the same extent (41 and 40%, respectively; P < 0.05 for both), without showing an additive effect. Amino-oxyacetate abolished infarct reduction by IPC and glutamate, and increased infarct size in both control and IPC hearts in a dose-dependent manner. Ischaemic preconditioning increased [GLUT](i) before ischaemia (P < 0.01) and decreased the release of glutamate during the first 10 min of reperfusion (P = 0.03). A twofold reduction in [GLUT](i) from the preischaemic state to 45 min of reperfusion (P = 0.0001) suggested increased postischaemic glutamate utilization in IPC hearts. While IPC and AOA changed haemodynamics in accordance with infarct size, glutamate decreased haemodynamic recovery despite reduced infarct size. In conclusion, ischaemic cardioprotection of the normal and IPC-protected heart depends on amino acid transamination and activity of the malate-aspartate shuttle during reperfusion. Underlying mechanisms of IPC include myocardial glutamate metabolism.
authors.affiliation: Department of Cardiology B, Arhus University Hospital, Skejby, 8200 Arhus N, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Løfgren
authors.forename: Jonas Agerlund
authors.initials: JA
authors.lastname: Povlsen
authors.forename: Lars Ege
authors.initials: LE
authors.lastname: Rasmussen
authors.forename: Nicolaj Brejnholt
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Lasse
authors.initials: L
authors.lastname: Solskov
authors.forename: Peter-Martin
authors.initials: PM
authors.lastname: Krarup
authors.forename: Steen Buus
authors.initials: SB
authors.lastname: Kristiansen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
authors.forename: Torsten Toftegaard
authors.initials: TT
authors.lastname: Nielsen
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002316:Cardiotonic Agents; D000625:Aminooxyacetic Acid; D018698:Glutamic Acid