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

P>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. 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. 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). 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.