Cardioprotective effect of L-glutamate in obese type 2 diabetic Zucker fatty rats

Clin Exp Pharmacol Physiol. 2009 Sep;36(9):892-8. doi: 10.1111/j.1440-1681.2009.05166.x. Epub 2009 Mar 2.

Abstract

1. Because diabetic hearts have an increased threshold for cardioprotection by ischaemic preconditioning (IPC), we hypothesized that protection by L-glutamate during reperfusion is restricted in Type 2 diabetic hearts. Previously, we found that L-glutamate-mediated postischaemic cardioprotection mimics IPC. 2. Rat hearts were studied in a Langendorff preparation perfused with Krebs'-Henseleit solution and subjected to 40 min global no-flow ischaemia, followed by 120 min reperfusion. L-Glutamate (0, 15 and 30 mmol/L) was added to the perfusate during reperfusion of hearts from non-diabetic (Wistar-Kyoto) and diabetic (Zucker diabetic fatty (ZDF)) rats, studied at 16 weeks of age. The infarct size (IS)/area-at-risk (AAR) ratio was the primary end-point. Expression of L-glutamate excitatory amino acid transporter (EAAT) 1 (mitochondrial) and EAAT3 (sarcolemmal) was determined by quantitative polymerase chain reaction and immunoblotting. 3. The ISS/AAR ratio did not differ between control hearts from Wistar-Kyoto and ZDF rats (0.52 ± 0.03 and 0.51 ± 0.04, respectively; P = 0.90). L-Glutamate (15 mmol/L) significantly reduced the IS/AAR ratio in non-diabetic hearts, but not in diabetic hearts, compared with their respective controls. The higher concentration of L-glutamate (30 mmol/L) reduced infarct size in diabetic hearts to the same degree as in non-diabetic hearts (IS/AAR 0.35 ± 0.03 (P = 0.002) and 0.34 ± 0.03 (P = 0.004), respectively). The mitochondrial L-glutamate transporter EAAT1 was downregulated in hearts from ZDF rats at both the mRNA and protein levels (P < 0.0005 and P < 0.0001, respectively). However, there was no change in EAAT3 expression at the protein level. Myocardial L-glutamate content was increased by 43% in diabetic hearts (P < 0.0001). 4. Hearts from obese diabetic rats have an elevated threshold for metabolic postischaemic cardioprotection by L-glutamate. These findings may reflect underlying mechanisms of inherent resistance against additional cardioprotection in the diabetic heart.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cardiotonic Agents / pharmacology*
  • Diabetes Complications / etiology
  • Diabetes Complications / genetics
  • Diabetes Complications / metabolism
  • Diabetes Complications / pathology
  • Diabetes Complications / physiopathology
  • Diabetes Complications / prevention & control*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Transporter 1 / genetics
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Excitatory Amino Acid Transporter 3 / genetics
  • Excitatory Amino Acid Transporter 3 / metabolism
  • Glutamic Acid / pharmacology*
  • Hemodynamics / drug effects
  • Male
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Myocardial Infarction / etiology
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / etiology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Obesity / complications*
  • Perfusion
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred WKY
  • Rats, Zucker
  • Sarcolemma / drug effects
  • Sarcolemma / metabolism
  • Time Factors
  • Ventricular Function, Left / drug effects

Substances

  • Cardiotonic Agents
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 3
  • RNA, Messenger
  • Slc1a1 protein, rat
  • Slc1a3 protein, rat
  • Glutamic Acid