ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03626.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTMyocardial ischemia results in two major alterations in cellular metabolism that eventually may affect every cellular function. The primary and major alteration is a decrease in oxidative production of ATP and consequently a decrease in all ATP dependent processes as cellular ATP declines to very low levels. The second alteration is accumulation of metabolic products secondary to both decreased coronary flow (washout) and decreased oxidative metabolism. High levels of metabolic products result in inhibition of several enzymatic reactions. Glycolytic inhibition by high NADH results in the loss of anaerobic ATP production. Inhibition of β‐oxidation by high levels of NADH and FADH2results in a accumulation of long‐chain acyl CoA and acylcarnitine esters and free fatty acids. These compounds are very active detergents and may alter several membrane functions such as Na+K+ATPase, and sarcoplasmic reticular, Ca++‐stimulated ATPase. Inaddition, the structure and function of mitochondria may be disrupted. Long‐chain acyl CoA is an effective inhibitor of lipolysis which may contribute to triglyceride accumulation in ischemic hearts.It is well known that K+arrest and hypothermia prevents many of the detrimental effects of ischemia. Tissue levels of high energy phosphates and the ability of the heart to recover mechanical function with reperfusion are preserved for much longer periods during hypothermic than during normothermic, hypoxic arrest. Other metabolic consequences of hypothermia and K+arrest were studied in isolated rat hearts. Hypothermia (10°C) without ischemia completely inhibited glycolysis and reduced fatty acid oxidation to about 7% of the normothermic rate. This suggests that attempts to improve energy production by ischemic tissue during hypothermia will not be successful. Hypothermia (10°C) with ischemia not only preserved ATP levels but reduced tissue levels of lactate, acyl CoA and acylcarnitine and increased tissue glycogen. These observations suggest that hypothermia decreases energy production to the same extent as energy utilization and tissue stores of high‐energy phosphates are preserved. In addition, the lack of accumulation of metabolic products decreases the potential for damage to membranes and metabolic pathways. Low levels of lactate and NADH coupled with high levels of glycogen provides a condition for rapid glycolytic rates with reperfusion a

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03627.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTHigh energy phosphate (HEP) utilization and depletion as well as the production and distribution of catabolic products of adenine nucleotides were studied in ischemic dog hearts in order to characterize the transition from reversible to irreversible cell injury. Severe ischemia, induced by coronary occlusionin vivowas compared to total ischemia,in vitro. Much of the creatine phosphate (CP) was lost within the first one to three minutes. During severe ischemiain vivo, adenosine triphosphate (ATP) was depleted to only 35% of control by 15 minutes (when myocytes are still reversibly injured) and to less than 10% by 40 minutes (at which time irreversible injury has occurred). HEP production from anaerobic glycolysis was estimated from the rate of accumulation of myocardial lactate. HEP production ceased when the ATP was less than 0.4 μmol/g wet weight (control = 5–6). Prior to this time, 80% of the HEP which had been utilized in ischemia had been derived from anaerobic glycolysis whereas 20% came from pre‐existing stores of CP and ATP.ATP depletion was paralleled by dephosphorylation of adenine nucleotides. The lost nucleotides were recovered stoichiometrically as adenosine, inosine, hypoxanthine, and xanthine in both models of ischemia. When myocardium was reperfused after 15 minutes of ischemia, these nucleosides and bases were lost to the systemic circulation, and repletion of adenine nucleotides was incomplete for as long as four days, apparently because bothde novoand salvage pathways of adenine nucleotide synthesis are slow in myocardium.Further studies were done to assess the nature of the associations between the decreasing ATP of the ischemic tissue and the onset of defects in high energy phosphate regeneration, cell volume and ion regulation, and/or membrane permeability. Slices of control tissue from tissue injured by various periods of total ischemia were incubated in oxygenated Krebs Ringer's phosphate medium containing14C‐inulin. As long as the ATP of the tissue was not depleted below 5 μmoles/g dry weight prior to incubation, no cellular abnormalities were detected. However, lower ATP levels were associated with depressed high energy phosphate resynthesis and failure of cell volume regulation. Overt membrane damage, as measured by an increased inulin diffusible space, was detected after the tissue ATP content decreased to less than 2.0 μmoles/g dry weight. Thus, cellular viability (reversible injury) was retained despite a modest and persistent ATP depletion, but there was a close assocation between marked ATP depletion and the failure of the damaged tissue to regenerate high energy phosphates and to preserve cell volume and ionic regulation (irreversible

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03628.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTIn acute coronary occlusion the survival time of ischemic myocardium depends critically upon collateral blood flow and on oxygen uptake at the moment of, and during, occlusion. There are good reasons to believe that ischemic myocardium provides the stimulus for near‐maximal vasodilation of collateral blood vessels. Under these conditions the determinants of collateral blood flow are: a) the anatomically fixed hydraulic resistance of the collaterals proper, b) the arterial driving pressure, c) extravascular resistance (radial stress, pressure transmission across the LV‐wall, tissue pressure) and d) size of the ischemic bed. Under ideal conditions (maximal dilation of collaterals) overall collateral resistance is 3.5 resistance units, i.e. theoretically a perfusion pressure of 350 mmHg is needed to drive 100ml of blood per minute through 100g of tissue. Small ischemic beds receive a relatively larger amount of collateral flow and vice versa. This delays necrosis (but does not prevent it) following occlusion of small coronary arteries. The reason for this is the more favorable ratio of epicardial circumference (of the ischemic area) to ischemic volume because canine collaterals are exclusively located on the epicardial surface. ‐ Tissue pressure in acute occlusion is distributed in such a way that subendocardial collateral flow is lower than subepicardial flow. This leads to an earlier onset of irreversible damage in the subendocardium, earlier damage to subendocardial microvessels, i.e. earlier subendocardial no‐reflow phenomenon. Flow «offered» to but not «taken» by the subendocardium is at the disposal of the subepicardium which thereby increases its chances of survival. As a rule subendocardial flow decreases as a function of time after occlusion and subepicardial flow increases. In certain cases even subepicardial flow is too low shortly after occlusion. In this case it decreases further with time and a truly transmural infar

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03629.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTThe rather static concept of a potentially salvageable ‘border zone’ of intermediate injury surrounding an area of regional ischemia would no longer seem tenable. This model, which has formed the basis for many approaches to therapeutic infarct size reduction, fails to take adequate account of a number of important factors including the dynamic nature of the ischemic process, the anatomy of the coronary microcirculation and the practical realities of tissue salvage. There is considerable evidence, from a number of species, that spatially identifiable border zones of intermediate injury do not exist, at least in the lateral plane. The apparent absence of a zone of target tissue does not necessitate the abandonment of concepts of myocardial protection but may require a major reapprai

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03630.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03631.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTThe survival of ischemic myocardium is critically dependent on effective adjustments between myocardial residual flow and energy requirement in the ischemic regions. The quantitative and qualitative changes for optimal adjustments may be studied in diving animals, normally exposed to long periods of hypoxemia and anaerobiosis.A series of studies have therefore been performed in seals in order to examine the regulations of myocardial blood flow, metabolism and left ventricular mechanics during diving asphyxia.Unanesthetized animals instrumented with catheters in the left ventricle and in the coronary sinus were submerged for periods of 10 to 16 minutes. The heart rate decreased from 135 to 12 beats/minute. End diastolic and systolic ventricular pressures were almost unchanged while LVdP/dt was reduced by 25%. Myocardial distance gauges implanted in the left ventricular wall showed that left ventricular dimensions during diastole and systole remained essentially constant. Consequently dilatation of the heart and developed wall tension were strictly controlled during diving asphyxia. Average myocardial blood flow, determined by microsphere injections, decreased to 10% of predive values and remained constant during the dive.Animals instrumented with mineature flow probes on the left circumflex coronary artery demonstrated that blood flow during diving ceases abruptly after the animal is submerged.Small bursts of flow are periodically observed in steadily increasing magnitude at 30 to 45 second intervals throughout dives lasting up to 15 minutes. The progressive reduction in arterial oxygen content was associated with a time dependent increase in myocardial lactate and hydrogen ion production. Glucose extraction was reduced while free fatty acid extraction remained unchanged. Following restoration of breathing a reactive myocardial hyperemia was observed along with an immediate return to myocardial uptake of lactate. Arterial lactate concentration increased temporarily after emergence. Despite increased glycolytic activity throughout the dive, coronary flow distribution was fully controlled and no evidence of ischemic dilatation of the left ventricle or ST‐segment elevation in the electrocardiogram was observed. Thus, coronary flow during diving was regulated jointly by a marked reduction in myocardial oxygen requirement (metabolic) and vasoconstrictor control (neurogenic).Glycolytic energy production became increasingly important througout the dive and was not associated with depressed myocardial function. These adaptations to diving asphyxia in the seal myocardium permit a reduction of coronary blood flow which is comparable to that in the infarcted dog myocardium, and therefore have relevance for therapeutic approaches to reduction of myocardial ischemic injury in ma

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03632.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTSeveral lines of evidence indicate that metabolites accumulating in ischemic tissue may have a profound influence on membrane function and may thereby mediate many of the electrophysiological derangements characteristic of ischemic tissuein vivo. Recently, we have detected the accumulation of lysophosphoglycerides (LPG), intermediate metabolites of membrane phospholipids, in ischemic tissuein vivo, in effluents from ischemic isolated hearts and in venular effluents from ischemic regionsin vivo. Furthermore, LPG, at comparable concentrations, induces reversible electrophysiological alterations in normoxic Purkinje fibers and ventricular muscle invitroclosely analogous to those changes characteristicof ischemic tissue in vivo. Concentration‐dependentchanges seeninclude a reduction in restingpotential,Vmaxof phase 0, action potential duration and amplitude, with profound decreases in conduction velocity, heterogenous phase 0 depolarization,enhancedautomaticity at reduced membrane potentials, and post‐repolarization refractoriness.Experimentsutilizing14C‐lysophosphatidyl choline (14C‐LPG) indicated that incorporation by LPC to a level of less than 1% of total cellular phospholipid is sufficient to induce electrophysiological derangements inisolated ventricular muscle. Based on the observations that venular effluents fromischemic regionsin vivoexert deleterious electrophysiological effects in vitro, we have recently demonstrated a two‐fold increase in LPC in venular effluents from ischemic regions in vitro. at Although this two‐fold increase did not produce significant electrophysiological effects in vitro at normal pH, concomitant acidosis (pH = 6.7) comparable to that seen during ischemia in vivo, resulted in dramatic electrophysiological derangements after exposure to LPC. Subsequent experiments indicated that acidosis alone had modest electrophysiological effects but decreased the LPC concentrations three‐fold required to induce membrane effects but did not enhance the incorporation of14C‐LPC into the cellular phospholipid fraction. Since long‐chain acyl carnitine also accumulate in ischemic myocardium and are also amphiphilic metabolites with many structural similarities to LPC, the effects of these compounds were also assessed in vitro. Palmitoyl carnitine at concentrations identical to LPC, induced electrophysiological derangements similar to LPC. In addition, the effects of the two compounds were additive and as with LPC, acidosis (pH = 6.7) decreased three‐fold the concentration of palmitoyl carnitine required to induce membrane derangements. The additive nature of the effects of these two different amphi

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03633.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

摘要:

ABSTRACTProfound alterations in metabolism occur within the first few minutes of myocardial ischaemia which may induce or modulate myocardial electrophysiological abnormalities and arrhythmogenesis, Fatty acid oxidation is inhibited with accumulation of long‐chain acyl CoA esters and glycolysis is stimulated but later inhibited. This may be worsened by a peripheral sympathetic response. In particular regional variations in glycolytic ATP productions which can modulate «slow channel» ion flux and hence slow conducting «slow response» potential activity, could influence patterns of slowed conduction in ischaemic myocardium of importance in generating early re‐entrant arrhythmias.This possibility has been examined in open chest anaesthetised dogs following experimental coronary occlusion by detailed computer aided analysis and construction of three dimensional maps of regional metabolism, blood flow and epicardial activation patterns at the time of early ventricular arrhythmias. Activation patterns were obtained using an electronic multiplexing system, flow using tracer microspheres and metabolic changes by analysis of multiple tissue samples for lactate and indices of glycolytic activity after rapid excision and freezing of the heart. Marked spacial inhomogeneities in flow, lactate and glycolytic activity were associated with delayed and fragmented activation in the central ischaemic region. Within the border region of flow, however, glycolytic activity was enhanced and conduction generally little impaired.It is suggested that transient changes in the homogeneity of myocardial metabolism and flow are critical in determining patterns of conduction and hence arrhythmogenesis. This may provide a basis for understanding anti‐arrhythmic effects of metabolic inte

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03634.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY

ISSN:0001-6101    

DOI:10.1111/j.0954-6820.1981.tb03635.x

出版商:Blackwell Publishing Ltd    

年代:1981

数据来源: WILEY