Povlsen, Jonas Agerlund6; Løfgren, Bo7; Rasmussen, Lars Ege4; Nielsen, Jan Møller4; Nørregaard, Rikke8; Kristiansen, Steen Buus4; Bøtker, Hans Erik6; Nielsen, Torsten Toftegård4
1 Department of Clinical Medicine - The Department of Cardiological Medicine B, Department of Clinical Medicine, Health, Aarhus University2 Department of Clinical Medicine - Center for Akutforskning, Department of Clinical Medicine, Health, Aarhus University3 Department of Clinical Medicine - Biomedical Radio Isotope Techniques, Department of Clinical Medicine, Health, Aarhus University4 The Department of Cardiological Medicine B, Faculty of Health Sciences, Aarhus University, Aarhus University5 Department of Clinical Medicine, Health, Aarhus University6 Department of Clinical Medicine - The Department of Cardiological Medicine B, Department of Clinical Medicine, Health, Aarhus University7 Department of Clinical Medicine - Center for Akutforskning, Department of Clinical Medicine, Health, Aarhus University8 Department of Clinical Medicine, Health, Aarhus University
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.
Clinical and Experimental Pharmacology and Physiology, 2009, Vol 36, Issue 9, p. 892-8