Article ; Online: Cardio-protective effects of combined l-arginine and insulin: Mechanism and therapeutic actions in myocardial ischemia-reperfusion injury.
European journal of pharmacology
2015 Volume 769, Page(s) 64–70
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. ... ...
| 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. |
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| MeSH term(s) | Animals ; Arginine/metabolism ; Arginine/pharmacology ; Biological Transport/drug effects ; Cardiotonic Agents/pharmacology ; Cell Hypoxia/drug effects ; Drug Interactions ; Insulin/pharmacology ; Intracellular Space/drug effects ; Intracellular Space/metabolism ; Male ; Mice ; Myocardial Reperfusion Injury/drug therapy ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Oxygen/metabolism ; Rats |
| Chemical Substances | Cardiotonic Agents ; Insulin ; Arginine (94ZLA3W45F) ; Oxygen (S88TT14065) |
| Language | English |
| Publishing date | 2015-12-15 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 80121-5 |
| ISSN | 1879-0712 ; 0014-2999 |
| ISSN (online) | 1879-0712 |
| ISSN | 0014-2999 |
| DOI | 10.1016/j.ejphar.2015.10.046 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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