title: Cardio-protective effects of combined l-arginine and insulin: Mechanism and therapeutic actions in myocardial ischemia-reperfusion injury.
abstract: Reduced nitric oxide (NO) bioavailability plays a central role in the pathogenesis of myocardial ischemia-reperfusion injury (I-R), and reduced l-arginine transport via cationic amino acid transporter-1 is a key contributor to the reduced NO levels. Insulin can increase NO levels by increasing the transport of its substrate l-arginine but insulin alone exerts minimal cardiac protection in I-R. We hypothesized that combined insulin and l-arginine may provide cardioprotective effects in the setting of myocardial I-R. The effect of supplemental insulin, l-arginine and the combination was examined in cardiomyocytes exposed to hypoxia/reoxygenation and in isolated perfused mouse hearts undergoing ischemia/reperfusion. When compared to controls, cardiomyocytes treated upon reoxygenation with 1nM insulin+1mM l-arginine exhibited significant (all P<0.05) improvements in NO generation and mitochondrial membrane potential, with a concomitant fall in reactive oxygen species production and LDH release. Insulin also increased l-arginine uptake following hypoxia-reoxygenation (P<0.05; n=4-6). In langendorff perfused isolated mouse hearts, combined l-arginine-insulin treatment upon reperfusion significantly (all P<0.05; n=9-11) improved recovery of left ventricular developed pressure, rate pressure product and end diastolic pressure following ischemia, independent of any changes in post-ischemic coronary flow, together with significantly lower LDH release. The observed improvements were greater than l-arginine or insulin treatment alone. In isolated cardiomyocytes (n=3-5), 1nM insulin caused cationic amino acid transporter-1 to redistribute to the cellular membrane from the cytosol and the effects of insulin on l-arginine uptake were partially dependent on the PI3K/Akt pathway. l-arginine-insulin treatment may be a novel strategy to ameliorate I-R injury.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Venardos
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Niwanthi W
authors.initials: NW
authors.lastname: Rajapakse
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Heart Foundation Research Centre, School of Medical Science, Griffith University, Gold Coast, Australia.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Hoe
authors.affiliation: Heart Foundation Research Centre, School of Medical Science, Griffith University, Gold Coast, Australia.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Peart
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia. Electronic address: david.kaye@bakeridi.edu.au.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D004347:Drug Interactions; D007328:Insulin / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D051381:Rats
chemical_list: D002316:Cardiotonic Agents; D007328:Insulin; D001120:Arginine; D010100:Oxygen
keywords: Cardiac ischemia reperfusion injury; Insulin; L-arginine transport; Nitric oxide