Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion

Abstract

The efficacy of increasing glycolysis during ischemia for enhancing the salutary effects of reperfusion was evaluated in isolated perfused rabbit hearts subjected to low-flow ischemia followed by reperfusion. Control hearts were perfused with buffer containing 0.4 mM palmitate, 5 mM glucose, and 70 mU/l insulin. Additional groups of hearts were perfused with double glucose/insulin and 1 mM dichloroacetate or were subjected to substrate priming to increase preischemic glycogen content. Ischemic contracture was completely prevented in hearts perfused with high glucose/insulin and was delayed markedly by either dichloroacetate or enhanced preischemic glycogen [45 +/- 14 and 31 +/- 20 min, respectively; P < 0.01 each vs. control (11 +/- 10 min)] and inversely related to the rate of lactate production. With reperfusion, recovery of developed pressure was 56 +/- 23% of baseline in control hearts, 90 +/- 8% in hearts receiving high glucose/insulin, 92 +/- 5% in hearts receiving dichloroacetate, and 79 +/- 19% in hearts with increased glycogen (P < 0.05 each vs. control hearts). Creatine kinase release was reduced by > 55% in treated hearts. Thus enhancement of glycolysis by diverse mechanisms during ischemia decreased ischemic damage and improved the recovery of contractile function with reperfusion.

Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion

“…This rate was chosen to raise the steady-state 13 C enrichments of plasma glucose and its myocardial intermediary metabolite pools to levels sufficient for precise measurement without raising plasma glucose concentration. As originally demonstrated by Lewandowski and others, 4,9 during continuous infusion of D- [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glucose, the myocardial pyruvate pool accumulates [3-13 C]pyruvate in proportion to that fraction of total glycolytic substrate contributed by circulating glucose relative to other carbon sources (eg, 12 C-glycogen). Myocardial concentrations of pyruvate are generally too low for its 13 C enrichment to be measured in small samples, but pyruvate is in equilibrium through transaminase reactions with the larger alanine pool.…”

“…Total GS activity was defined as that observed at saturating (7.2 mmol/L) glucose-6-phosphate. Similarly, physiological (GP-a) and total GP activities were measured as the rates of incorporation of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glucose-1-phosphate into glycogen in the absence and presence, respectively, of 5 mmol/L adenosine monophosphate. Activities are reported as the fraction of total activity present in the GS-i or GP-a forms.…”

“…For example, in the isolated perfused heart, glycolysis accelerates acutely during ischemia to allow anaerobic ATP formation. 1,2 The provision of extra glycolytic substrate either during ischemia 1,3 or during early reperfusion 4 may improve short-term functional recovery; alternatively, the inhibition of glycolysis with 2-deoxyglucose 5 or excess fatty acids 6 delays or prevents it.…”

Miocárdio hibernante: uma realidade clínica

“…Em parte, isso decorre do fato de não se dispor de modelo experimental satisfatório para estudo dos mecanismos fisiopatogênicos íntimos implicados. Algumas pesquisas têm usado preparação aproximativa da hibernação, por períodos curtos, e seus resultados, complementados por observações histopatológicas em humanos, comprovaram vários aspectos [11][12][13][14][15][16][17][18] : 1) não ocorre redução dos ní-veis de fosfatos altamente energéticos; 2) intensifica-se o metabolismo glicolítico, provavelmente atenuando os efeitos da isquemia; 3) os transientes de Ca ++ encontram-se deprimidos, ao menos em estágios iniciais do processo de hibernação; 4) acú-mulo de glicogênio miocitário é observado em está-gios mais avançados; 5) verifica-se nítido processo de desdiferenciação miocitária, com perda de sarcômeros, também em fases mais adiantadas; 6) de forma muito intrigante, mantém-se reserva inotrópica, que pode ser recrutada por estimulação adrenérgica.…”

Glucose-insulin-potassium treatment in combination with dipyridamole inhibits ischaemia-reperfusion-induced damage

“…The beneficial effects of high dose glucose-insulinpotassium (GIK) infusion have been reported in reperfused patients after by pass graft surgery [1], in stable coronary artery disease [2], after acute myocardial infarction [3,4] and during pacing stress testing [5]. GIK exert beneficial effects on the ischaemic heart by reducing infarct size, improving post ischaemic left ventricular function and reducing mortality in myocardial infarction by 28 % [6].…”