CARDIOPROTECTIVE EFFECT OF l-GLUTAMATE IN OBESE TYPE 2 DIABETIC ZUCKER FATTY RATS

• 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.