CARDIOPROTECTION BY l‐GLUTAMATE DURING POSTISCHAEMIC REPERFUSION: REDUCED INFARCT SIZE AND ENHANCED GLYCOGEN RESYNTHESIS IN A RAT INSULIN‐FREE HEART MODEL

Abstract

1. Previously, we found that administration of high-dose L-glutamate during postischaemic reperfusion improves haemodynamic recovery and enhances glycogen resynthesis. In the present study, we investigated whether the same effect occurs in an insulin-free model and whether glutamate administration reduces infarct size. Further, we studied whether the cardioprotective effect of glutamate depends on preserved glutamate transamination and K(ATP) channel activity. 2. In a rat isolated, insulin-free, perfused heart model, we compared the effects of administration of L-glutamate (10 mmol/L) during either 45 min no-flow regional ischaemia plus 120 min reperfusion or reperfusion alone on infarct size and left ventricular (LV) recovery. The effect of glutamate on glycogen metabolism was studied in a model of 30 min global no-flow ischaemia and 60 min reperfusion. In both models, the effects of inhibition of glutamate transamination and K(ATP) channel activity were examined by adding amino-oxyacetate (an aminotransferase inhibitor; 0.1 mmol/L) and glibenclamide (a K(ATP) blocker; 10 mmol/L), respectively. 3. Administration of L-glutamate reduced infarct size by 60% (P < 0.01) and improved postischaemic LV function (developed pressure and rate pressure product; P < 0.05). L-Glutamate increased glycogen content after 60 min reperfusion by 65% (P < 0.01). Amino-oxyacetate, as well as glibenclamide, abolished the glutamate-mediated reduction in infarct size, haemodynamic improvement and glycogen resynthesis during reperfusion. 4. In conclusion, L-glutamate administration from the start of postischaemic reperfusion exerts cardioprotective effects, including reduced infarct size, improved haemodynamic recovery and enhanced glycogen resynthesis. These effects depend on preserved transamination of glutamate and K(ATP) channel activity, but not on insulin administration.

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

“…Interestingly, this drop in ATP content was fully counteracted by glutamate administration in the first hour of reoxygenation. In connection with these results, a previous work by Kristiansen and coworkers showed that, in a rat isolated perfused heart model, the administration of exogenous glutamate from the beginning of the reperfusion reduces infarct size to the same extent as its administration during both ischemia and reperfusion, indicating that glutamate main effect is linked to the latter phase 5 . Additionally, we found that the NCX1 inhibitor SN-6 abolished the ability of glutamate to ameliorate ATP production.…”

“…First, at the concentration tested in this study, glutamate has no evident toxic effect on H9c2 cells and rat adult cardiomyocytes. Second, protection against ischemic injury typically requires glutamate supplementation in the millimolar range 5,6,38,50 . Third, although glutamate has very large muscle/plasma ratios at the baseline, during myocardial ischemia such large concentration gradient dissipates 4 and high exogenous concentrations of glutamate are required to compensate this loss and enable adequate intracellular glutamate loading 6 .…”

“…In particular, interventions during the reperfusion are feasible strategies for cardioprotection, and the resumption of the aerobic metabolism through the provision of energy substrates is one of the most promising approach 4 . In this regard, experimental and clinical evidence suggest that glutamate supplementation has the potential to protect myocardium against I/R injury 5–7 . Glutamate is a key molecule in cellular metabolism 8,9 : it can fuel respiration and participate as anaplerotic substrate to maintain optimum levels of Krebs cycle intermediates, which are typically compromised in the ischemic heart 10,11 , or even provide cellular energy through substrate level phosphorylation reactions 4 .…”

Glutamate protects against Ca2+ paradox‐induced injury and inhibits calpain activity in isolated rat hearts

“…The function of glutamate in the heart has been a focus of research since the discovery of its decrease in ischaemia‐reperfusion injury . Many studies have demonstrated that the replenishing of glutamate mitigates myocardial ischaemia‐reperfusion injury, which manifests as attenuated infarcts and improved heart function recovery . Other studies have demonstrated that glutamate did not improve heart function after arrest or significantly decrease 30‐day mortality and myocardial infarcts in patients undergoing heart surgery despite shortening the median intensive care unit stay and decreasing the incidence of severe circulatory failure .…”

“…9 Many studies have demonstrated that the replenishing of glutamate mitigates myocardial ischaemia-reperfusion injury, which manifests as attenuated infarcts and improved heart function recovery. [10][11][12] Other studies have demonstrated that glutamate did not improve heart function after arrest or significantly decrease 30-day mortality and myocardial infarcts in patients undergoing heart surgery despite shortening the median intensive care unit stay and decreasing the incidence of severe circulatory failure. 13,14 It is currently accepted that glutamate transporters are a primary cause of the protective effects of glutamate via maintenance of its intracellular content and energy metabolism, [15][16][17][18] which results in improved intracellular Ca 2+ handling.…”