Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the e... more Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the essence of a complex series of molecular reactions triggered by the sudden reduction or cessation of blood flow to the heart. We recognize that it is difficult to describe even simple metabolic changes occurring in ischemia without a brief recap of pathways of energy transfer in the normal myocardium. We will therefore begin with a description of the energy substrate supply to a system that is best defined as the heart's remarkable ability for efficient conversion of chemical into mechanical energy. At the core of the system are rates of oxidative phosphorylation of adenosine diphosphate (ADP) that exactly match rates of adenosine triphosphate (ATP) hydrolysis. We will then describe the consequences of a sudden interruption to this balance, namely ischemia. At the same time we will explore metabolic strategies that may be employed to lessen the consequences of ischemia on contractile function, highlighting areas of future research and clinical investigation. The review is not meant to be comprehensive. Its main aim is to discuss the concept of pharmacotherapy as an intervention in altered cellular metabolism, akin to the concept of reperfusion therapy as an intervention in obstructed coronary arteries.
Journal of Molecular and Cellular Cardiology, Dec 31, 1996
Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture... more Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture in an isolated perfused rat heart, but improves recovery of function. The preconditioning ischaemic episode is also known to deplete glycogen stores. We tested whether a depletion in glycogen is related to the protection conferred by preconditioning. The isolated Langendorff perfused rat heart, with a left ventricular balloon to record function, was perfused with either glucose 11 mM, acetate 5 mM, or glucose 11 mM + insulin to alter pre-ischaemic glycogen levels prior to 30 min total global ischaemia. In addition, hearts were preconditioned by an episode of 5 min ischaemia and 5 min reperfusion. Time to onset of contracture (TOC-min), peak contracture and recovery of developed pressure after 20 min reperfusion with glucose-containing perfusate (both expressed as percentage pre-ischaemic developed pressure) were measured (n = 9-10). Parallel groups of hearts were clamped at various times for assessment of tissue metabolites. Acetate pre-perfusion reduced glycogen levels compared to glucose hearts, from 16.27 +/- 0.44 to 10.77 +/- 0.96 mumol/g wet wt. TOC was reduced and peak contracture increased, with poor functional recovery. Glucose + insulin pre-perfusion increased glycogen (21.39 +/- 1.08 mumol/g wet wt) with opposite effects on contracture, but functional recovery was still poor. Preconditioning hastened the time to onset of contracture, which could be partially attributed to glycogen depletion. Preconditioning significantly improved functional recovery in glucose hearts, but had little or no effect in the other groups. Thus the protective effect on functional recovery could not be linked to glycogen depletion. Pre-ischaemic glycogen appeared to play a dual role. When low, preconditioning was ineffective, presumably because of lack of production of glycolytic ATP, and severe contracture. When pre-ischaemic glycogen was increased, preconditioning was also relatively ineffective, presumably because of excess accumulation of the metabolites of glycogenolysis.
ABSTRACT Key words necrosis Preconditioning - ischemia - reperfusion - tioning can have different... more ABSTRACT Key words necrosis Preconditioning - ischemia - reperfusion - tioning can have different end-points, and that not all of its effects are favourable. Specifically, there may be adverse effects during the ischaemic period, which differ from those on reperfusion.
The Journal of thoracic and cardiovascular surgery, 1991
The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, c... more The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, can be detrimental. We added either 100% nitrogen, 95% nitrogen and 5% carbon dioxide, 100% oxygen, or 95% oxygen and 5% carbon dioxide to the cardioplegic solution (St. Thomas' Hospital No. 2 plus glucose 11 mmol/L), and determined postischemic recovery of isolated rat hearts after 3 hours of 10 degrees C cardioplegic protected ischemia. Hearts were arrested and reinfused every 30 minutes throughout the ischemic period with cardioplegic solution. When 5% carbon dioxide was added to nitrogen, the pH of the cardioplegic solution decreased from 9.1 (100% nitrogen) to 7.0 (95% nitrogen: 5% carbon dioxide), a change associated with improved postischemic functional recovery. Aortic output improved from 52.3% +/- 2.7% to 63.9% +/- 2.8%, p less than 0.05, and cardiac output from 60.8% +/- 3.6% to 75.4% +/- 3.3%, p less than 0.01. This improvement was associated with diminished efflux of lact...
The Journal of thoracic and cardiovascular surgery, 1991
The intention of this study was to determine whether glucose is beneficial in a cardioplegic solu... more The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart, with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore, a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 m...
American journal of physiology. Heart and circulatory physiology, 2001
To determine whether the effects of fatty acids on the diabetic heart during ischemia involve alt... more To determine whether the effects of fatty acids on the diabetic heart during ischemia involve altered glycolytic ATP and proton production, we measured energetics and intracellular pH (pH(i)) by using (31)P NMR spectroscopy plus [2-(3)H]glucose uptake in isolated rat hearts. Hearts from 7-wk streptozotocin diabetic and control rats, perfused with buffer containing 11 mM glucose, with or without 1.2 mM palmitate or the ketone bodies, 4 mM beta-hydroxybutyrate plus 1 mM acetoacetate, were subjected to 32 min of low-flow (0.3 ml x g wet wt(-1) x min(-1)) ischemia, followed by 32 min of reperfusion. In control rat hearts, neither palmitate nor ketone bodies altered the recovery of contractile function. Diabetic rat hearts perfused with glucose alone or with ketone bodies, had functional recoveries 50% lower than those of the control hearts, but palmitate restored recovery to control levels. In a parallel group with the functional recoveries, palmitate prevented the 54% faster loss of AT...
Experimentally, enhanced glycolytic flux has been shown to confer many benefits to the ischemic h... more Experimentally, enhanced glycolytic flux has been shown to confer many benefits to the ischemic heart, including maintenance of membrane activity, inhibition of contracture, reduced arrhythmias, and improved functional recovery. While at moderate low coronary flows, the benefits of glycolysis appear extensive, the controversy arises at very low flow rates, in the absence of flow; or when glycolytic substrate may be present in excess, such that high glucose concentrations with or without insulin overload the cell with deleterious metabolites. Under conditions of total global ischemia, glycogen is the only substrate for glycolytic flux. Glycogenolysis may only be protective until the accumulation of metabolites (lactate, H+, NADH, sugar phosphates and Pi ) outweighs the benefit of the ATP produced. The possible deleterious effects associated with increased glycolysis cannot be ignored, and may explain some of the controversial findings reported in the literature. However, an optimal b...
The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the ... more The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R.
Journal of Molecular and Cellular Cardiology, 1996
Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture... more Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture in an isolated perfused rat heart, but improves recovery of function. The preconditioning ischaemic episode is also known to deplete glycogen stores. We tested whether a depletion in glycogen is related to the protection conferred by preconditioning. The isolated Langendorff perfused rat heart, with a left ventricular balloon to record function, was perfused with either glucose 11 mM, acetate 5 mM, or glucose 11 mM + insulin to alter pre-ischaemic glycogen levels prior to 30 min total global ischaemia. In addition, hearts were preconditioned by an episode of 5 min ischaemia and 5 min reperfusion. Time to onset of contracture (TOC-min), peak contracture and recovery of developed pressure after 20 min reperfusion with glucose-containing perfusate (both expressed as percentage pre-ischaemic developed pressure) were measured (n = 9-10). Parallel groups of hearts were clamped at various times for assessment of tissue metabolites. Acetate pre-perfusion reduced glycogen levels compared to glucose hearts, from 16.27 +/- 0.44 to 10.77 +/- 0.96 mumol/g wet wt. TOC was reduced and peak contracture increased, with poor functional recovery. Glucose + insulin pre-perfusion increased glycogen (21.39 +/- 1.08 mumol/g wet wt) with opposite effects on contracture, but functional recovery was still poor. Preconditioning hastened the time to onset of contracture, which could be partially attributed to glycogen depletion. Preconditioning significantly improved functional recovery in glucose hearts, but had little or no effect in the other groups. Thus the protective effect on functional recovery could not be linked to glycogen depletion. Pre-ischaemic glycogen appeared to play a dual role. When low, preconditioning was ineffective, presumably because of lack of production of glycolytic ATP, and severe contracture. When pre-ischaemic glycogen was increased, preconditioning was also relatively ineffective, presumably because of excess accumulation of the metabolites of glycogenolysis.
Journal of Molecular and Cellular Cardiology, 1995
Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen e... more Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen et al., 1990). However, accumulation of harmful metabolic end products may inhibit glycolytic flux and lessen the benefit of glucose. We assessed whether during increasingly severe flow restriction, provision of glucose might be harmful rather than beneficial, using the Langendorff perfused rat heart. Ischemic contracture (resting tension expressed as percent of preischemic developed pressure) was measured via a left ventricular balloon. Reductions in flow to 0, 0.015, 0.03, 0.06, 0.1, 0.2 or 0.4 ml/min/g wet wt over 60 min were tested. At zero flow, peak contracture was 61.4 +/- 3.5% (+/- S.E.) but fell to 15.6 +/- 6.3% with 0.4 ml/min/g wet wt (P < 0.05) in the presence of 11 mmol/l glucose. Time-to-onset of contracture was significantly delayed by the higher coronary flows. At coronary flows down to zero, the effect of glucose was inconstant or absent, but not harmful. With the residual flow at 0.2 ml/min/g wet wt, a dose response to glucose in ischemia was elicited, using concentrations of 0, 2.5, 5.5, 11 or 22 mmol/l. Maximum protection against ischemic contracture was found with 11 mmol/l glucose. However, once contracture occurred, functional recovery was severely impaired in all cases. Reducing glycogen prior to low flow ischemia (0.2 ml/min/g wet wt) with 11 mmol/l glucose increased peak contracture, and reduced the time-to-onset of contracture. Increased preischemic glycogen had little effect on contracture. Glycolytic flux fell in proportion to the coronary flow. However, there was an increased glucose extraction at lower flows of 0.1 and 0.2 ml/min/g wet wt, suggesting that it is the rate of delivery (i.e. coronary flow) which is the rate limiting step rather than enzyme inhibition by accumulated metabolites. If flow were further reduced, metabolite accumulation would become more important, such that with no flow, this would be the determinant of glycolytic flux rate. In our model, the two requirements for optimal protection from ischemia were (i) provision of glucose (11 mmol/l was optimal) and (ii) an adequate coronary flow to deliver the glucose and remove end product inhibition (greater than 0.06 ml/min/g wet wt).
Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pres... more Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pressure of both oxygen (O2) and carbon dioxide (CO2). Therefore, oxygenating St. Thomas' Hospital II plus glucose (11 mmol/L) cardioplegic solution with 95% O2 + 5% CO2 induces a pH shift to 7.0 (10 degrees C) as opposed to pH 9.3 with 100% O2. In an isolated working rat heart model, we show that pH 7.0 (10 degrees C) improves mechanical postischemic recovery in the absence or presence of O2. However, in the absence of O2, pH 7.0 appears to inhibit glycolysis and diminish the stability of cellular membranes. The provision of O2 independently improved mechanical recovery and at pH 7.0, improved the preservation of the sarcolemma. Increasing the O2 content by including a perfluorocarbon (FC-43) in the oxygenated St. Thomas' plus glucose cardioplegia is not additionally beneficial. St. Thomas' Hospital plus glucose cardioplegic solution should be oxygenated, but with 95% O2 + 5% CO2 and not 100% O2.
Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the e... more Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the essence of a complex series of molecular reactions triggered by the sudden reduction or cessation of blood flow to the heart. We recognize that it is difficult to describe even simple metabolic changes occurring in ischemia without a brief recap of pathways of energy transfer in the normal myocardium. We will therefore begin with a description of the energy substrate supply to a system that is best defined as the heart's remarkable ability for efficient conversion of chemical into mechanical energy. At the core of the system are rates of oxidative phosphorylation of adenosine diphosphate (ADP) that exactly match rates of adenosine triphosphate (ATP) hydrolysis. We will then describe the consequences of a sudden interruption to this balance, namely ischemia. At the same time we will explore metabolic strategies that may be employed to lessen the consequences of ischemia on contractile function, highlighting areas of future research and clinical investigation. The review is not meant to be comprehensive. Its main aim is to discuss the concept of pharmacotherapy as an intervention in altered cellular metabolism, akin to the concept of reperfusion therapy as an intervention in obstructed coronary arteries.
Journal of Molecular and Cellular Cardiology, Dec 31, 1996
Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture... more Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture in an isolated perfused rat heart, but improves recovery of function. The preconditioning ischaemic episode is also known to deplete glycogen stores. We tested whether a depletion in glycogen is related to the protection conferred by preconditioning. The isolated Langendorff perfused rat heart, with a left ventricular balloon to record function, was perfused with either glucose 11 mM, acetate 5 mM, or glucose 11 mM + insulin to alter pre-ischaemic glycogen levels prior to 30 min total global ischaemia. In addition, hearts were preconditioned by an episode of 5 min ischaemia and 5 min reperfusion. Time to onset of contracture (TOC-min), peak contracture and recovery of developed pressure after 20 min reperfusion with glucose-containing perfusate (both expressed as percentage pre-ischaemic developed pressure) were measured (n = 9-10). Parallel groups of hearts were clamped at various times for assessment of tissue metabolites. Acetate pre-perfusion reduced glycogen levels compared to glucose hearts, from 16.27 +/- 0.44 to 10.77 +/- 0.96 mumol/g wet wt. TOC was reduced and peak contracture increased, with poor functional recovery. Glucose + insulin pre-perfusion increased glycogen (21.39 +/- 1.08 mumol/g wet wt) with opposite effects on contracture, but functional recovery was still poor. Preconditioning hastened the time to onset of contracture, which could be partially attributed to glycogen depletion. Preconditioning significantly improved functional recovery in glucose hearts, but had little or no effect in the other groups. Thus the protective effect on functional recovery could not be linked to glycogen depletion. Pre-ischaemic glycogen appeared to play a dual role. When low, preconditioning was ineffective, presumably because of lack of production of glycolytic ATP, and severe contracture. When pre-ischaemic glycogen was increased, preconditioning was also relatively ineffective, presumably because of excess accumulation of the metabolites of glycogenolysis.
ABSTRACT Key words necrosis Preconditioning - ischemia - reperfusion - tioning can have different... more ABSTRACT Key words necrosis Preconditioning - ischemia - reperfusion - tioning can have different end-points, and that not all of its effects are favourable. Specifically, there may be adverse effects during the ischaemic period, which differ from those on reperfusion.
The Journal of thoracic and cardiovascular surgery, 1991
The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, c... more The hypothesis tested is that shifts in pH, induced when a cardioplegic solution is oxygenated, can be detrimental. We added either 100% nitrogen, 95% nitrogen and 5% carbon dioxide, 100% oxygen, or 95% oxygen and 5% carbon dioxide to the cardioplegic solution (St. Thomas' Hospital No. 2 plus glucose 11 mmol/L), and determined postischemic recovery of isolated rat hearts after 3 hours of 10 degrees C cardioplegic protected ischemia. Hearts were arrested and reinfused every 30 minutes throughout the ischemic period with cardioplegic solution. When 5% carbon dioxide was added to nitrogen, the pH of the cardioplegic solution decreased from 9.1 (100% nitrogen) to 7.0 (95% nitrogen: 5% carbon dioxide), a change associated with improved postischemic functional recovery. Aortic output improved from 52.3% +/- 2.7% to 63.9% +/- 2.8%, p less than 0.05, and cardiac output from 60.8% +/- 3.6% to 75.4% +/- 3.3%, p less than 0.01. This improvement was associated with diminished efflux of lact...
The Journal of thoracic and cardiovascular surgery, 1991
The intention of this study was to determine whether glucose is beneficial in a cardioplegic solu... more The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart, with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore, a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 m...
American journal of physiology. Heart and circulatory physiology, 2001
To determine whether the effects of fatty acids on the diabetic heart during ischemia involve alt... more To determine whether the effects of fatty acids on the diabetic heart during ischemia involve altered glycolytic ATP and proton production, we measured energetics and intracellular pH (pH(i)) by using (31)P NMR spectroscopy plus [2-(3)H]glucose uptake in isolated rat hearts. Hearts from 7-wk streptozotocin diabetic and control rats, perfused with buffer containing 11 mM glucose, with or without 1.2 mM palmitate or the ketone bodies, 4 mM beta-hydroxybutyrate plus 1 mM acetoacetate, were subjected to 32 min of low-flow (0.3 ml x g wet wt(-1) x min(-1)) ischemia, followed by 32 min of reperfusion. In control rat hearts, neither palmitate nor ketone bodies altered the recovery of contractile function. Diabetic rat hearts perfused with glucose alone or with ketone bodies, had functional recoveries 50% lower than those of the control hearts, but palmitate restored recovery to control levels. In a parallel group with the functional recoveries, palmitate prevented the 54% faster loss of AT...
Experimentally, enhanced glycolytic flux has been shown to confer many benefits to the ischemic h... more Experimentally, enhanced glycolytic flux has been shown to confer many benefits to the ischemic heart, including maintenance of membrane activity, inhibition of contracture, reduced arrhythmias, and improved functional recovery. While at moderate low coronary flows, the benefits of glycolysis appear extensive, the controversy arises at very low flow rates, in the absence of flow; or when glycolytic substrate may be present in excess, such that high glucose concentrations with or without insulin overload the cell with deleterious metabolites. Under conditions of total global ischemia, glycogen is the only substrate for glycolytic flux. Glycogenolysis may only be protective until the accumulation of metabolites (lactate, H+, NADH, sugar phosphates and Pi ) outweighs the benefit of the ATP produced. The possible deleterious effects associated with increased glycolysis cannot be ignored, and may explain some of the controversial findings reported in the literature. However, an optimal b...
The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the ... more The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R.
Journal of Molecular and Cellular Cardiology, 1996
Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture... more Preconditioning hastens the time to onset of ischaemic contracture and increases peak contracture in an isolated perfused rat heart, but improves recovery of function. The preconditioning ischaemic episode is also known to deplete glycogen stores. We tested whether a depletion in glycogen is related to the protection conferred by preconditioning. The isolated Langendorff perfused rat heart, with a left ventricular balloon to record function, was perfused with either glucose 11 mM, acetate 5 mM, or glucose 11 mM + insulin to alter pre-ischaemic glycogen levels prior to 30 min total global ischaemia. In addition, hearts were preconditioned by an episode of 5 min ischaemia and 5 min reperfusion. Time to onset of contracture (TOC-min), peak contracture and recovery of developed pressure after 20 min reperfusion with glucose-containing perfusate (both expressed as percentage pre-ischaemic developed pressure) were measured (n = 9-10). Parallel groups of hearts were clamped at various times for assessment of tissue metabolites. Acetate pre-perfusion reduced glycogen levels compared to glucose hearts, from 16.27 +/- 0.44 to 10.77 +/- 0.96 mumol/g wet wt. TOC was reduced and peak contracture increased, with poor functional recovery. Glucose + insulin pre-perfusion increased glycogen (21.39 +/- 1.08 mumol/g wet wt) with opposite effects on contracture, but functional recovery was still poor. Preconditioning hastened the time to onset of contracture, which could be partially attributed to glycogen depletion. Preconditioning significantly improved functional recovery in glucose hearts, but had little or no effect in the other groups. Thus the protective effect on functional recovery could not be linked to glycogen depletion. Pre-ischaemic glycogen appeared to play a dual role. When low, preconditioning was ineffective, presumably because of lack of production of glycolytic ATP, and severe contracture. When pre-ischaemic glycogen was increased, preconditioning was also relatively ineffective, presumably because of excess accumulation of the metabolites of glycogenolysis.
Journal of Molecular and Cellular Cardiology, 1995
Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen e... more Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen et al., 1990). However, accumulation of harmful metabolic end products may inhibit glycolytic flux and lessen the benefit of glucose. We assessed whether during increasingly severe flow restriction, provision of glucose might be harmful rather than beneficial, using the Langendorff perfused rat heart. Ischemic contracture (resting tension expressed as percent of preischemic developed pressure) was measured via a left ventricular balloon. Reductions in flow to 0, 0.015, 0.03, 0.06, 0.1, 0.2 or 0.4 ml/min/g wet wt over 60 min were tested. At zero flow, peak contracture was 61.4 +/- 3.5% (+/- S.E.) but fell to 15.6 +/- 6.3% with 0.4 ml/min/g wet wt (P < 0.05) in the presence of 11 mmol/l glucose. Time-to-onset of contracture was significantly delayed by the higher coronary flows. At coronary flows down to zero, the effect of glucose was inconstant or absent, but not harmful. With the residual flow at 0.2 ml/min/g wet wt, a dose response to glucose in ischemia was elicited, using concentrations of 0, 2.5, 5.5, 11 or 22 mmol/l. Maximum protection against ischemic contracture was found with 11 mmol/l glucose. However, once contracture occurred, functional recovery was severely impaired in all cases. Reducing glycogen prior to low flow ischemia (0.2 ml/min/g wet wt) with 11 mmol/l glucose increased peak contracture, and reduced the time-to-onset of contracture. Increased preischemic glycogen had little effect on contracture. Glycolytic flux fell in proportion to the coronary flow. However, there was an increased glucose extraction at lower flows of 0.1 and 0.2 ml/min/g wet wt, suggesting that it is the rate of delivery (i.e. coronary flow) which is the rate limiting step rather than enzyme inhibition by accumulated metabolites. If flow were further reduced, metabolite accumulation would become more important, such that with no flow, this would be the determinant of glycolytic flux rate. In our model, the two requirements for optimal protection from ischemia were (i) provision of glucose (11 mmol/l was optimal) and (ii) an adequate coronary flow to deliver the glucose and remove end product inhibition (greater than 0.06 ml/min/g wet wt).
Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pres... more Oxygenation of a bicarbonate-containing crystalloid cardioplegic solution alters the partial pressure of both oxygen (O2) and carbon dioxide (CO2). Therefore, oxygenating St. Thomas' Hospital II plus glucose (11 mmol/L) cardioplegic solution with 95% O2 + 5% CO2 induces a pH shift to 7.0 (10 degrees C) as opposed to pH 9.3 with 100% O2. In an isolated working rat heart model, we show that pH 7.0 (10 degrees C) improves mechanical postischemic recovery in the absence or presence of O2. However, in the absence of O2, pH 7.0 appears to inhibit glycolysis and diminish the stability of cellular membranes. The provision of O2 independently improved mechanical recovery and at pH 7.0, improved the preservation of the sarcolemma. Increasing the O2 content by including a perfluorocarbon (FC-43) in the oxygenated St. Thomas' plus glucose cardioplegia is not additionally beneficial. St. Thomas' Hospital plus glucose cardioplegic solution should be oxygenated, but with 95% O2 + 5% CO2 and not 100% O2.
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