Onset Of Ischemic Contracture Research Articles

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice.

ObjectiveSodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice.Methods and ResultsWe determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin-perfused hearts.ConclusionsCardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI.

Microtubule stabilization with paclitaxel does not protect against infarction in isolated rat hearts

What is the central question of this study? The microtubule network is disrupted during myocardial ischaemia-reperfusion injury. It was suggested that prevention of microtubule disruption with paclitaxel might reduce cardiac infarct size; however, the effects on infarction have not been studied. What is the main finding and its importance? Paclitaxel caused a reduction in microtubule disruption and cardiomyocyte hypercontracture during ischaemia-reperfusion. However, it induced a greater increase in cytosolic calcium, which may explain the lack of effect against infarction that we have seen in isolated rat hearts. The large increase in perfusion pressure induced by paclitaxel in this model may have clinical implications, because detrimental effects of the drug were reported after its clinical application. Microtubules play a major role in the transmission of mechanical forces within the myocardium and in maintenance of organelle function. However, this intracellular network is disrupted during myocardial ischaemia-reperfusion. We assessed the effects of prevention of microtubule disruption with paclitaxel on ischaemia-reperfusion injury in isolated rat cardiomyocytes and hearts. Isolated rat cardiomyocytes were submitted to normoxia (1 h) or 45 min of simulated ischaemia (pH 6.4, 0% O2 , 37 °C) and reoxygenation, without or with treatment with the microtubule stabilizer, paclitaxel (10(-5) M), or the inhibitor of microtubule polymerization, colchicine (5 × 10(-6) M). Simulated ischaemia leads to microtubule disruption before the onset of ischaemic contracture. Paclitaxel attenuated both microtubule disruption and the incidence of hypercontracture, whereas treatment with colchicine mimicked the effects of simulated ischaemia and reoxygenation. In isolated normoxic rat hearts, treatment with paclitaxel induced concentration-dependent decreases in heart rate and left ventricular developed pressure and increases in perfusion pressure. Despite protection against hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37 ± 2.27% in control hearts versus 58.75 ± 10.25, 55.44 ± 10.32 and 50.06 ± 10.14% after treatment with 10(-6) , 3 × 10(-6) and 10(-5) m of paclitaxel) after 60 min of global ischaemia and reperfusion in isolated rat hearts. Lack of protection was correlated with a higher increase in cytosolic calcium levels during simulated ischaemia in cardiomyocytes treated with paclitaxel (2.32 ± 0.15 versus 1.13 ± 0.16 a.u. in the presence or absence of 10(-6) m paclitaxel, respectively, P < 0.05), but not with changes in aortic reactivity. In conclusion, microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts.

Abstract 15175: Critical Role of Sodium-Glucose Cotransporter 1 in the Cardioprotection Through the Maintenance of Energy Production During Ischemia-Reperfusion Injury

Glucose becomes an important preferential substrate for cardiac metabolism and ATP generation under specific pathological conditions, such as ischemia. Glucose utilization is initiated by glucose uptake, which is mainly controlled by glucose transporters. Although the role of passive glucose transporters (GLUTs) has been investigated intensively, little is known about the functional significance of the other active transporter, sodium-glucose cotransporter 1 (SGLT1), in the heart. We herein hypothesized that cardiac SGLT1 plays a critical role for cardioprotection during ischemia-reperfusion injury (IRI), possibly through the enhanced glucose utilization for the energy production. To test this, we studied the effects of 10-4 M of phlorizin, SGLT1 inhibitor, on the baseline function and its response to global ischemia (20 minutes)-reperfusion (40 minutes) injury in mouse Langendorff perfusion model, where SGLT1, but not SGLT2, is highly expressed, as confirmed by immunoblotting assay. Although phlorizin did not affect baseline function, its administration during IRI significantly impaired recovery in left ventricular contraction (% recovery of baseline; 67.3±4.5 vs. 89.7±6.8%, n=5 each, P&lt;0.05) and rate pressure product (18600±1290 vs. 25100±1010 mmHg•bpm, n=5 each, P&lt;0.01), associated with increased infarct size demonstrated by TTC staining as well as CPK activity released into the perfusate (20.8±9.5 vs. 2.0±0.6 U•g, n≥3, P&lt;0.05). Of note, the onset of ischemic contracture, which is thought to be initiated by ATP depletion in cardiomyocytes, was earlier with phlorizin perfusion (288±21 vs. 364±27 sec, n≥8, P&lt;0.05). Consistent with this, the significant reduction of tissue ATP content was observed in phlorizin perfused heart (4.81±0.61 vs. 6.87±0.13 μmol/g tissue, n≥4, P&lt;0.05). In conclusion, these data demonstrate that SGLT1 represents an important cardioprotective mechanism against IRI possibly through the maintenance of ATP generation. Our findings shed new light on the essential role of SGLT1 for the optimization of cardiac energy metabolism by the enhanced glucose availability during ischemia, thus leading to substantial myocardial protection after severe ischemic insults.

Abstract 2316: Ranolazine, a Late Sodium Current Inhibitor, as an Adjunct to Cardioplegia Further Reduces Contracture during Ischemia and Reperfusion

Although cardioplegia (CP) protects myocardium during ischemic cardiac arrest, cardioplegic preservation can be suboptimal for increasingly complex cardiac surgical patients. Ranolazine (Ran), a novel antianginal agent, was recently shown to mitigate ischemia-induced Ca 2+ overload via its inhibitory effects on the late Na + current, but the benefit of Ran during cardioplegic arrest is not known. The purpose of the study was to investigate the therapeutic potential of Ran as an adjunct to CP. Hearts isolated from female Sprague-Dawley rats were Langendorff-perfused and exposed to normothermic global ischemia for 40 min followed by 30-min reperfusion (I/R). Three groups were studied: control buffer (n = 10); crystalloid CP (Fremes, n = 12); CP supplemented with Ran (n = 12). CP was bolus-injected with or without Ran at the time of ischemia. End-diastolic pressure (EDP), developed pressure, dP/dt min , and dP/dt max were measured throughout the study. CP significantly delayed onset of ischemic contracture (defined as a time to 20 mmHg of EDP), compared to control (25 ± 2 min in CP alone vs. 12 ± 1 min in control, p &lt; 0.05). Ran added to CP further delayed the time to contracture (34 ± 2 min in Ran, p &lt; 0.05 compared to CP alone). Consistent with these findings, the area under the diastolic pressure curve during the entire period of ischemia was significantly smaller in CP + Ran versus CP alone (p &lt; 0.05). I/R caused dramatic elevations in EDP during reperfusion. CP lessened the extent of the reperfusion contracture (32 ± 3 mmHg in CP alone vs. 76 ± 3 mmHg in control, p &lt; 0.05). Addition of Ran to CP further lessened the contracture (17 ± 2 mmHg in Ran, p &lt; 0.05 compared to CP alone). I/R severely depressed systolic cardiac contractile function. The impairment in contractile function was significantly reduced by CP, as well as CP + Ran, but there was no statistical difference between the two groups. While CP alone reduced the onset of cardiac contracture in this model of I/R, addition of Ran to CP further enhanced the cardioprotection. These results suggest the potential therapeutic efficacy of Ran as an adjunct to CP and further support the protective role of late Na + current inhibition.

Chronic heat improves mechanical and metabolic response of trained rat heart on ischemia and reperfusion.

Cardiac mechanics and metabolic performance were studied in isolated perfused hearts of rats subjected to a combined chronic stress of heat acclimation and swimming training (EXAC) or swimming training alone (EX). Diastolic (DP) and systolic pressures (SP), coronary flow (CF), and oxygen consumption were measured during normoperfusion (80 mmHg), and the appearance of ischemic contracture (IC), DP, and SP were measured during progressive graded ischemia, total ischemia (TI), and reperfusion insults. ATP, phosphocreatine, and intracellular pH were measured during TI and reperfusion with 31P nuclear magnetic resonance spectroscopy. During normoperfusion, SP and cardiac efficiency (derived from rate-pressure product-oxygen consumption relationships) were the highest in the 2-mo EXAC hearts (P < 0.0001). During progressive graded ischemia, the development of IC (percentage of total hearts) was similar in both EXAC and EX hearts; the only significant difference was confined to the 1- vs. 2-mo groups. The onset of IC was delayed in the EXAC hearts and, on reperfusion, recovery, particularly of DP, was significantly improved in the latter. After TI, EXAC hearts retained 30% of the ATP pool and there was a delayed decline in intracellular pH. On reperfusion, these hearts also displayed improved ATP and phosphocreatine recovery, the 2-mo EXAC heart demonstrating significantly faster high-energy phosphate salvage, improved diastolic function, and pulse pressure recovery. The data attest to the beneficial effects of heat acclimation on cardiac mechanics of trained rats during normoperfusion and cardiac protection on ischemia and reperfusion. Possibly, energy sparing, lesser acidosis, and shorter duration of IC on ischemia and improved energy salvage on reperfusion contribute synergistically to this potent beneficial effect.

R56865 is antifibrillatory in reperfused ischemic guinea-pig hearts, even when given only during reperfusion

R56865 was previously characterized as an inhibitor of Na and Ca overload that has beneficial effects during ischemia and reperfusion. An isolated guinea-pig heart preparation was subjected to 60 minutes of ischemia and 60 minutes of reperfusion. R56865 was given before ischemia and with the onset of reperfusion, applying different dosing schedules, including an initial loading dose. R56865 below 0.1 mumol/l had no cardiodepressant effects in normoxic hearts and at 0.1 mumol/l reduced left ventricular pressure marginally. The onset of ischemic contracture was delayed only at this concentration. R56865 given before ischemia potently inhibits delayed sustained fibrillation occurring during reperfusion in the concentration range between 0.01 mumol/l and 0.1 mumol/l. Analysis of cellular Na+, K+, and Ca2+ concentrations revealed that R56865 substantially improves the ionic homeostasis of myocardial cells. Most importantly, the compound also reduced the incidence of delayed sustained fibrillation when given at the onset of reperfusion. R56865 was most effective when fast equilibration of drug with tissue was achieved by giving an initial loading dose. In particular, the cellular Na+ and Ca2+ contents were improved using this dosing scheme. The results are compatible with the classification of R56865 as an inhibitor of Na+ and Ca2+ overload.

Hyperpolarized Arrest Attenuates Myocardial Stunning Following Global Surgical Ischemia: An Alternative to Traditional Hyperkalemic Cardioplegia?

There is clinical evidence that myocardial stunning is a frequent sequela of surgical global ischemia, despite our modern techniques of myocardial protection. The ubiquitous usage of hyperkalemic depolarizing solutions in all forms of cardioplegia may be partly responsible for this phenomenon because of the known ongoing metabolic requirements and damaging transmembrane ionic fluxes that occur at depolarized membrane potentials. Cardiac arrest at hyperpolarized potentials, the natural resting state of the heart, may avoid the shortcomings of depolarized arrest and provide an alternative means of myocardial protection. To test this hypothesis, a potassium channel opener, aprikalim, was used to induce hyperpolarized arrest in an isolated rabbit heart model. Aprikalim was able to produce sustained and reproducible electromechanical arrest that was reversible by reperfusion. When compared with depolarized hyperkalemic arrest, hyperpolarized arrest afforded better protection after short 20-minute periods of global ischemia and resulted in less myocardial stunning. Moreover, aprikalim was able to significantly prolong the time to ischemic contracture and improve functional recovery after the onset of ischemic contracture when compared with either traditional hyperkalemic cardioplegia or no cardioplegia at all. There was a dose dependence to the protective effect of aprikalim. Preliminary studies in the intact porcine cardiopulmonary bypass model also have revealed that hyperpolarized arrest can effectively protect the heart during surgical global ischemia.

Heat acclimation improves cardiac mechanics and metabolic performance during ischemia and reperfusion.

Cardiac mechanics and metabolic performance were studied in isolated perfused hearts of heat-acclimated (AC) rats (at 34 degrees C for 1 mo) and their age-matched controls (C). Diastolic and systolic pressures, coronary flow, and the appearance of ischemic contracture (IC) were measured during progressive graded ischemia, total ischemia (TI), and reperfusion. ATP, phosphocreatine, and intracellular pH were measured during TI and reperfusion with the use of 31P-nuclear magnetic resonance spectroscopy. Systolic pressure was greater in AC hearts than in C hearts (P < 0.0001). During 50% of perfusion pressure 15 and 46% of AC and C hearts, respectively, showed IC (P < 0.001). During 25% of perfusion pressure 85% of the hearts in both groups developed IC. The onset of IC in AC hearts was delayed compared with in C hearts. On reperfusion 93 and 66% of AC and C hearts, respectively, resumed contraction. Recovery of diastolic pressure was 78 and 36% for the AC and C hearts, respectively (P < 0.05). During TI ATP declined by 0.94 and 1.20 mumol/min in AC and C hearts, respectively, resulting in 21 +/- 2.8% preservation of the ATP pool in AC hearts after 30 min of TI (P < 0.001). The AC group also showed a delayed decline in intracellular pH (P < 0.001). The data suggest beneficial effects of heat acclimation on the heart, which were exhibited by greater pressure generation and by the emergence of protecting features during ischemia and reperfusion, possibly via energy-sparing mechanisms.

Effects of glibenclamide and nicorandil on cardiac function during ischemia and reperfusion in isolated perfused rat hearts

We examined influences of a blocker (glibenclamide) and an opener (nicorandil) of the ATP-sensitive potassium (KATP) channel on extracellular K concentration [( K+]e), as well as the myocardial function and metabolites during global ischemia and reperfusion in Langendorff-perfused rat heart preparation. In control hearts, [K+]e began to rise 20 s after the onset of ischemia up to an initial peak (8.3 +/- 0.3 mM) at 2.5 +/- 0.7 min, then fell to 6.0 +/- 0.8 mM after 8.2 +/- 0.7 min, and then rose progressively to 14.6 +/- 0.8 mM at the end of 30 min of ischemia. Glibenclamide (50 microM) reduced the initial peak of [K+]e to 7.2 +/- 0.3 mM (P less than 0.01), and nicorandil (200 microM) increased it to 9.4 +/- 0.6 mM (P less than 0.01). There were no significant differences in [K+]e values among all groups at the end of ischemia. During ischemia, nicorandil decreased the time to mechanical arrest from 1.9 +/- 0.1 min to 1.5 +/- 0.1 min, whereas it was increased by glibenclamide to 2.7 +/- 0.4 min. In control hearts, the time to onset of ischemic contracture was 14.7 +/- 1.8 min. Nicorandil delayed onset of contracture and glibenclamide accelerated it. Thus we have confirmed that some part of the early increase in [K+]e during ischemia is attributable to K+ efflux through the KATP channel in our model, and opening of the KATP channel may contribute to a rapid reduction of the contractility of the ischemic myocardium that subsequently protects the myocardium against further ischemic injury.

Accelerated transmural gradients of energy compound metabolism resulting from left ventricular hypertrophy

Eighteen dogs underwent transmural left ventricular biopsies for adenosine triphosphate and suturing of the noncoronary cusp, creating valvular aortic stenosis. Three months after aortic stenosis and the subsequent development of left ventricular hypertrophy, animals underwent repeat transmural left ventricular biopsies followed by total myocardial ischemia at 37 degrees C. Left ventricular tissue samples for adenosine triphosphate and lactate levels were determined at 15-minute intervals and compared with 15 control animals. No significant difference between subendocardial and subepicardial adenosine triphosphate levels was found between left ventricular samples taken before left ventricular hypertrophy and 3 months after left ventricular hypertrophy. Significant differences in adenosine triphosphate utilization occurred between subendocardial and subepicardial layers in control and left ventricular hypertrophy myocardium, however. The gradient between the subendocardium and the subepicardium was significantly increased by left ventricular hypertrophy (p less than 0.05). Significant differences also occurred within the same layer when left ventricular hypertrophy and control groups were compared. During total ischemia, lactate concentration was significantly greater within the subendocardium than within the subepicardium in left ventricular hypertrophy. The onset of ischemic contracture was 48.2 +/- 2.1 minutes in left ventricular hypertrophy versus 62.3 +/- 1.8 minutes in control hearts (p less than 0.01). Subendocardial intramyocardial pressure increased significantly earlier than subepicardial in both left ventricular hypertrophy and control hearts. Adenosine triphosphate was used, and lactate accumulated more rapidly in animals with a more pronounced hemodynamic gradient. These data show that after left ventricular hypertrophy, adenosine triphosphate stores in the subendocardium and the subepicardium are unchanged from control values, yet the rates of adenosine triphosphate utilization and lactate accumulation during total ischemia are significantly increased. Furthermore, the subendocardial to subepicardial gradient of adenosine triphosphate utilization during ischemia found in normal hearts is markedly increased by left ventricular hypertrophy.

Passive electrical properties, mechanical activity, and extracellular potassium in arterially perfused and ischemic rabbit ventricular muscle. Effects of calcium entry blockade or hypocalcemia.

The relation among passive electrical resistive properties, longitudinal conduction velocity, extracellular potassium concentration, [K+]o, and mechanical activity was investigated in the isolated rabbit papillary muscle during normal arterial perfusion and no-flow ischemia in the presence and absence of verapamil, or a reduced extracellular Ca2+ concentration [Ca2+]o. During normal arterial perfusion, verapamil (0.5 microM, free [Ca2+]o = 1.0 mM) and hypocalcemic blood perfusate (free [Ca2+]o = 0.4 mM) reduced the maximal isometric twitch tension by 48% and 78%, depolarized the resting membrane by +3 and +7 mV, decreased the extracellular longitudinal resistance (ro) by 15% and 26%, and increased conduction velocity by 4% and 6%, respectively. The changes in conduction velocity during these interventions were consistent with those predicted by linear cable theory (+3% and +9%) for the observed changes in ro. In contrast, verapamil shortened whereas a reduced [Ca2+]o lengthened action potential duration. Comparison of simultaneously measured longitudinal whole tissue resistance (rt), intracellular longitudinal resistance (ri), [K+]o, and resting tension during ischemia showed a close association between abrupt cell-to-cell electrical uncoupling, development of ischemic contracture, and the secondary rise of [K+]o, which all started to develop after approximately 15 minutes of ischemia. Electrical cell-to-cell uncoupling was completed within 15 minutes. In the presence of verapamil, the relation among the onset of electrical cell-to-cell uncoupling, secondary rise of [K+]o, and onset of ischemic contracture in ischemia was qualitatively the same as in its absence; however, these events were postponed by approximately 10 minutes, and the rates of contracture development and uncoupling were diminished. Conduction velocity decreased after 12 minutes of ischemia from 54 to 36 cm/sec in the absence of and from 61 to 46 cm/sec in the presence of verapamil. This slowing effect on impulse conduction could not be attributed to changes of electrical cell-to-cell coupling because at this time an increase in ri had not yet taken place. In the presence of a reduced [Ca2+]o, the resting tension and ri increased almost immediately after the onset of ischemia. Although the resting tension rose progressively throughout the course of ischemia, the ri showed a biphasic increase characterized by an early transient increase that reached a peak at 8 minutes (+87%) and a second, irreversible increase beginning at approximately 12 minutes. This final onset of electrical cell-to-cell uncoupling and the secondary rise of [K+]o were not different from the findings with a normal [Ca2+]o.(ABSTRACT TRUNCATED AT 400 WORDS)

Alterations in Oxidative Function and Respiratory Regulation in the Post-ischemic Myocardium

In the normal and post-ischemic, isovolumic Langendorff perfused rat hearts, 31P NMR spectra and mechanical performance were evaluated over a wide range of myocardial oxygen consumption rates (MVO2). Hearts were perfused with either glucose and insulin, palmitate and glucose, or pyruvate and glucose as exogenous carbon sources. After ischemia at 38 degrees C until the onset of ischemic contracture and subsequent reperfusion, the "free" ADP levels were significantly reduced as compared to controls. In the control palmitate + glucose and glucose + insulin groups, the ADP levels were virtually independent of approximately 2.5-fold variation in MVO2; in contrast, they changed 4-fold with a approximately 30% variation in MVO2 in the post-ischemic myocardium following ischemia to contracture. In the pyruvate + glucose group, ADP levels varied with MVO2 in controls and post-ischemia; however, MVO2-ADP relationship was significantly altered following ischemia. Analysis of these observations within the concept of kinetic regulation of oxidative phosphorylation yielded the following significant conclusions: 1) the mode of respiratory regulation changed from a non-ADP to an "ADP:Pi limited" domain with non-pyruvate carbon sources; 2) respiratory regulation was in the ADP:Pi limited domain before and after ischemia in the pyruvate + glucose group; however, the Km for the relationship between MVO2 and ADP was reduced following the ischemia/reperfusion insult; 3) the post-ischemic oxidative capacity (Vmax for MVO2) was significantly reduced in all groups and this reduction would limit maximal post-ischemic mechanical performance.

On-line Detection of Reversible Myocardial Ischemic Injury by Measurement of Myocardial Electrical Impedance

The metabolic and physiological alterations associated with changes in myocardial tissue electrical resistivity during ischemia were characterized to assess the feasibility of using such resistivity as an on-line indicator of the onset of ischemic injury. Twelve anesthetized dogs underwent rapid cardiac extirpation; 5 served as untreated controls, and 7 were preheated wth metoprolol tartrate. Beta blockade was used to alter the time course of ischemic injury as demonstrated previously in studies using this experimental model. In vitro measurement of myocardial resistivity, the detection of ischemic contracture, and serial measurements of tissue adenosine triphosphate (ATP) and lactate were obtained from totally ischemic left ventricles at 37°C. Myocardial resistivity began to increase significantly before onset of ischemic contracture in the untreated control group (resistivity at 42.3 ± 3.1 minutes, contracture at 53.8 ± 3.7 minutes; p < 0.025) as well as the metoprolol group (resistivity at 50.7 ± 1.5 minutes, contracture at 70.0 ± 3.5 minutes; p < 0.005). As expected, ischemic contracture was delayed in the beta-blocked group compared with controls ( p < 0.01). Similarly, the onset of myocardial resistivity increase was delayed in the beta-blocked group ( p < 0.025). ATP and lactate levels at the onset of myocardial resistivity increase were consistent with severe but reversible injury. Resistivity changes during ischemia correlated linearly with simultaneous ATP depletion and lactate accumulation ( r = 0.88 to 0.98; p < 0.05). Furthermore, during global ischemia studied in 3 anesthetized dogs in vivo, the onset of myocardial resistivity increase occurred after 20 minutes. Finally, 6 anesthetized dogs underwent 60 minutes of in vivo regional ischemia by coronary artery occlusion, followed by 60 minutes of reperfusion. Myocardial resistivity in the ischemic region increased immediately and steadily after coronary occlusion, followed by a rapid decrease during subsequent reperfusion. These data show that myocardial resistivity may be useful for identifying severe but still reversible ischemic injury in on-line fashion during regional and global myocardial ischemia.

Protective Metabolic Effects of Propranolol During Total Myocardial Ischemia

Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37° C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 ± 1.4 minutes compared with 75.9 ± 2.2 minutes in the propranolol-treated group (p

Effects of acute tachycardia on left ventricular adenine nucleotide levels and subsequent tolerance to ischemia

Electrophysiologically guided surgical procedures for the ablation of supraventricular and ventricular dysrhythmias often require prolonged periods of tachycardia to complete intraoperative mapping studies. It is unknown whether tachycardia depletes the myocardium of high-energy compounds or alters subsequent tolerance to ischemia. In the present study, 12 anesthetized dogs were paced from the right ventricle at a cycle length of 250 msec for 60 minutes. In seven animals, drill biopsy specimens were taken from the left ventricular free wall for analysis of adenine nucleotide levels and their breakdown products before and after pacing and after 20 minutes of recovery from pacing. In the remaining five animals, the heart was made totally ischemic immediately after tachycardia and the time to the onset of ischemic contracture was determined and compared to that of five nonpaced control dogs. Acute tachycardia resulted in no significant reduction in adenine nucleotide levels compared to control values. Furthermore, in hearts rendered totally ischemic after tachycardia, the mean time to ischemic contracture was 65.6 +/- 1.3 minutes versus 63.6 +/- 2 minutes in nonpaced control animals (no significant difference). These data show that pacing-induced tachycardia in the normal heart does not decrease adenine nucleotide levels or affect subsequent tolerance to ischemia. These results may be clinically relevant to patients without coronary artery disease who undergo operative procedures necessitating prolonged periods of tachycardia for intraoperative mapping to identify the site of arrhythmogenesis.

Protective metabolic effects of propranolol during total myocardial ischemia

Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37 degrees C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 +/- 1.4 minutes compared with 75.9 +/- 2.2 minutes in the propranolol-treated group (p less than 0.01). In addition to significantly delaying the onset of ischemic contracture, propranolol also decreased the rate of anaerobic glycolysis during ischemia. Ischemic contracture occurred in the control group with an average adenosine triphosphate level of 1.26 +/- 0.08 mumol compared to 0.91 +/- 0.08 mumol/gm wet weight for the beta blocked group (p less than 0.0025). These are the first data suggesting that the protective effects of beta blockade may be related to a beneficial effect on ischemic myocardial metabolism allowing myocardium to survive with lower levels of adenosine triphosphate.

Evidence that ischemic cell death begins in the subendocardium independent of variations in collateral flow or wall tension.

Irreversible ischemic injury occurs after coronary artery occlusion in vivo, first in the subendocardium and progressing toward the subepicardium over time, presumably due to transmural variations in collateral flow or wall tension. In this study, 10 left ventricular globally ischemic slabs were created that were free of wall tension and collateral flow. The onset and completion of ischemic contracture were identified by means of a new tissue compressibility gauge designed for these studies. Transmural samples were obtained at 15 min intervals for determination of high-energy nucleotide levels and for ultrastructural analysis. The results show that there is a statistically significant gradient of ATP depletion, with the subendocardium consistently showing accelerated energy utilization compared with the subepicardium (p less than .05). Ultrastructural evidence of irreversible injury first appeared in the subendocardium at the onset of ischemic contracture and occurred when ATP levels declined to less than 1 mumol/g wet weight. In summary, these data show that during total ischemia in vitro, cell death begins in the subendocardium at the onset of ischemic contracture and progresses toward the subepicardium over time. These changes occurred independent of variations in collateral flow or wall tension. The results suggest that the increased risk of the subendocardium to ischemic injury previously noted in vivo may occur not only because of variations in collateral flow and wall tension, but may also be secondary to an increased metabolic rate of the subendocardium resulting in faster ATP use during the period of ischemia.

The relationship of ischemic contracture to vascular reperfusion in the isolated rat heart

Isolated Langendorff rat heart preparations were used to measure ischemic contracture of the left ventricle by means of an intraventricular balloon catheter connected to a pressure recorder. After various times of global ischemia, the extent of reflow to the ventricles was visualized by perfusion with 1% fluorescein solution. The onset of ischemic contracture was accelerated and its magnitude increased by preischemic perfusion with 0.5 m m iodoacetate (IAA). Conversely, its onset was delayed and magnitude decreased by preischemic perfusion with buffer containing only 0.05 m m calcium. Compared with control hearts, those pretreated with the low calcium buffer showed more extensive reflow, whereas IAA-treated hearts showed a greater loss of vascular competence in the early stages of reperfusion. Although the reperfusion defect developed after ischemic contracture, its ultimate extent correlated closely with the force of contracture. It is proposed that subendocardial blood vessels closed by the tension generated in ischemic contracture, eventually lose their ability to dilate and allow reperfusion as compliance of the myocardium is reduced by the development of rigor mortis.