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R B Jennings

Publications and source records attributed to R B Jennings.

At least 73 records · Page 4Linked to original sources
PubMed1986

Effect of repetitive brief episodes of ischemia on cell volume, electrolytes and ultrastructure.

The effects of repeated brief episodes of ischemia on myocardial cell volume, electrolytes and ultrastructure were studied in dogs. Seventeen animals were divided into five groups. Group 1 underwent a single 10 minute occlusion of the circumflex coronary artery, with no subsequent reperfusion. Group 2 was similarly subjected to a 10 minute coronary occlusion, but was allowed a 20 minute reperfusion period. Group 3 underwent two 10 minute occlusions separated by 20 minutes of reperfusion and Group 4 underwent four 10 minute occlusions, each separated from the next by 20 minutes of reperfusion. Group 5 was subjected to a single, uninterrupted 40 minute occlusion. The anterior and posterior papillary muscles in each heart were sampled to compare nonischemic versus ischemic myocardium. No changes in myocardial water or electrolytes occurred during ischemia. However, reperfusion was associated with slight increases in tissue water and potassium, loss of magnesium and minimal changes in sodium or calcium ions. Electron microscopic analysis revealed signs of mild ischemic injury (absence of normal intramitochondrial granules, partial loss of glycogen and slight clumping of the nuclear chromatin) in posterior papillary muscle from Groups 1, 3 and 4. Group 2 showed complete recovery with 20 minutes of reperfusion, whereas Group 5 showed evidence of irreversible injury. There was no difference in the appearance of myocardium that had been subjected to one, two or four 10 minute occlusions. It is concluded that intermittent periods of reperfusion between brief episodes of coronary ischemia have a protective effect and prevent a cumulative deterioration of myocardial ultrastructure.

Adenosine Triphosphate↗
PubMed1986

Four brief periods of myocardial ischemia cause no cumulative ATP loss or necrosis.

The effect of repetitive periods of coronary occlusion on myocardial adenine nucleotides, lactate, and infarct size was studied. In one series of dogs, the circumflex artery was occluded for one, two, or four 10-min episodes, each separated by 20 min of reperfusion. Hearts were excised and sampled for metabolic assays after one or more periods of ischemia before or after reperfusion. One 10-min period of ischemia caused a 61% loss of ATP and 41% loss of adenine nucleotides from the most severely ischemic subendocardial zone. Reperfusion resulted in rapid restoration of the adenylate charge but in only slight repletion of the adenine nucleotide pool. However, two or even four 10-min periods of ischemia caused no further adenine nucleotide loss. In contrast, 40 min of continuous coronary occlusion caused an 87% depletion of ATP and 67% of the adenine nucleotide pool from the same subendocardial region. Collateral blood flow was similar during all occlusions, but lactate accumulation was less during later occlusions. In a second series of experiments, myocardial necrosis was quantitated 4 days after four 10-min periods of ischemia. Necrosis was observed in only one of six dogs and, in this dog, was only 1.5% of the anatomic area at risk. Thus intermittent reperfusion prevents cumulative metabolic deficits and myocardial ischemic cell death, perhaps by restoring the capacity for high-energy phosphate (HEP) production and/or washing out deleterious catabolites. A first episode of ischemia also slows HEP utilization in subsequent episodes.

Adenosine Diphosphate↗
PubMed1986

Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

We have previously shown that a brief episode of ischemia slows the rate of ATP depletion during subsequent ischemic episodes. Additionally, intermittent reperfusion may be beneficial to the myocardium by washing out catabolites that have accumulated during ischemia. Thus, we proposed that multiple brief ischemic episodes might actually protect the heart from a subsequent sustained ischemic insult. To test this hypothesis, two sets of experiments were performed. In the first set, one group of dogs (n = 7) was preconditioned with four 5 min circumflex occlusions, each separated by 5 min of reperfusion, followed by a sustained 40 min occlusion. The control group (n = 5) received a single 40 min occlusion. In the second study, an identical preconditioning protocol was followed, and animals (n = 9) then received a sustained 3 hr occlusion. Control animals (n = 7) received a single 3 hr occlusion. Animals were allowed 4 days of reperfusion thereafter. Histologic infarct size then was measured and was related to the major baseline predictors of infarct size, including the anatomic area at risk and collateral blood flow. In the 40 min study, preconditioning with ischemia paradoxically limited infarct size to 25% of that seen in the control group (p less than .001). Collateral blood flows were not significantly different in the two groups. In the 3 hr study, there was no difference between infarct size in the preconditioned and control groups. The protective effect of preconditioning in the 40 min study may have been due to reduced ATP depletion and/or to reduced catabolite accumulation during the sustained occlusion. These results suggest that the multiple anginal episodes that often precede myocardial infarction in man may delay cell death after coronary occlusion, and thereby allow for greater salvage of myocardium through reperfusion therapy.

Animals↗
PubMed1985

Effects of calcium-channel blockers on myocardial preservation during experimental acute myocardial infarction.

Calcium antagonists have become accepted agents for the attenuation of myocardial ischemia when it becomes manifest as angina pectoris. However, it is not known whether these agents can protect ischemic myocardium during the early evolution of an acute myocardial infarct. Calcium antagonists could potentially improve myocardial perfusion, by relieving coronary spasm or improving collateral blood flow, and reduce the energy demands of the ischemic myocardium either directly or by reducing heart rate or contractility. In some studies, calcium antagonists have decreased the rate of adenosine triphosphate depletion in ischemia and reduced functional or structural indexes of ischemic injury after relatively brief periods (up to 2 hours) of injury. We have assessed the ability of verapamil to protect severely ischemic myocardium in dogs with a 40-minute test period of circumflex occlusion followed by reperfusion. After 4 days of recovery, infarcts were sized by histologic methods. Untreated dogs had subendocardial infarcts (the more moderately ischemic subepicardial region being salvaged by reperfusion). Pretreatment with verapamil reduced the size of these subendocardial infarcts from 34 +/- 8 to 8 +/- 3% of the ischemic circumflex vascular bed (anatomic area at risk). Thus, verapamil prevented cell death in a substantial proportion of the severely ischemic subendocardial region that otherwise would have died as a result of the 40-minute test period of ischemia. To establish whether verapamil could prevent cell death for a longer period of time in the less severely ischemic subepicardial region, a 3-hour period of coronary occlusion with reperfusion was studied.

Animals↗
PubMed1985

Nucleotide metabolism and cellular damage in myocardial ischemia.

Adenine nucleotide metabolism is greatly altered by myocardial anoxia or ischemia, both of which induce depletion of ATP and of the total adenine nucleotide pool. The depletion occurs at variable rates depending upon the nature of the model and the severity and conditions of the injury. In ischemia, the decrease in both ATP and the adenine nucleotide pool is due to an inadequate rate of production of high-energy phosphate relative to the demand of the heart for energy. In the process of capturing the high-energy phosphate of ADP, AMP is produced via myokinase and is degraded to nucleosides and ultimately to bases. In the early phase of ischemia, ADO and INO are the chief metabolites produced. A small quantity of XAN and large quantities of HX accumulate with time until eventually HX replaces INO as the principal metabolite of the pool. The biology of myocardial ischemic cell damage in the dog heart is summarized with respect to the depletion of ATP and total adenine nucleotide pool. Myocytes can survive with about 25% of the ATP of control tissue but exhibit a variety of defects that persist for minutes to days. At the onset of irreversibility, the dead tissue invariably exhibits virtually no ATP and a 65% or greater depletion in the total adenine nucleotide pool. It is not known whether these changes in ATP and the pool are directly or indirectly related to the development of irreversibility. In any event, the transition to cell death appears to be gradual.

Adenine Nucleotides↗
PubMed1985

Unilateral renal vein occlusion in rats.

To study the relationship of renal vein thrombosis to membranous glomerulonephritis with the nephrotic syndrome, we attempted to simulate the former by occluding to 0.5 mm one renal vein in rats. Although increased proteinuria did occur during the first 3 days after such occlusion, there was little difference from control animals in the amount of proteinuria thereafter, up to 46 days, and no evidence of membranous glomerulonephritis by light, immunofluorescent, or electron microscopy.

Animals↗
PubMed1985

Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs.

During the acute phase of myocardial ischemia, adenine nucleotides are degraded to nucleosides and bases, especially inosine and hypoxanthine. Simultaneously, xanthine dehydrogenase is converted to xanthine oxidase, an enzyme that converts hypoxanthine to xanthine, and xanthine to uric acid, producing a superoxide anion for each molecule of hypoxanthine or xanthine oxidized. To determine if free radicals via this enzymatic source contribute to cell death in myocardial ischemia, we determined whether allopurinol, an inhibitor of xanthine oxidase, could limit infarct size in a reperfusion preparation of myocardial infarction. The circumflex coronary artery of each of 34 dogs was occluded for 40 min, followed by reperfusion for 4 days. Infarct size then was measured by histologic methods and was related to major baseline predictors of infarct size, including anatomic area at risk and collateral blood flow. Infarct size was larger (NS) in the allopurinol (n = 8) than in the control (n = 11) group, a trend that was related to slightly higher (NS) collateral blood flow in the control group. We conclude that allopurinol has no beneficial effect in this preparation of experimental myocardial infarction. The results oppose the hypothesis that free radicals, produced via the xanthine oxidase reaction, are an important contributing factor in myocardial ischemic cell death.

Allopurinol↗
PubMed1985

Effect of reperfusion late in the phase of reversible ischemic injury. Changes in cell volume, electrolytes, metabolites, and ultrastructure.

The acute effects of reperfusion on myocardium reversibly damaged by 15 minutes of severe ischemia in vivo, were studied. Changes in the adenine nucleotide pool, cell volume regulation, myocardial calcium, and ultrastructure were studied at the end of 15 minutes of ischemia and after 0.5, 3.0, and 20 minutes of reflow. Before reperfusion, adenosine triphosphate and the adenylate pool decreased by 63% and 44% of control, respectively, and the adenylate charge was reduced to 0.65. After 3 minutes of reperfusion, the adenylate charge was restored to control by the rephosphorylation of adenosine mono- and diphosphate, but adenosine triphosphate was still reduced by 45%. Mild tissue edema was detected after 0.5 minute of reflow and persisted throughout 20 minutes of reperfusion. The increased tissue water was accompanied by a slight increase in sodium and a marked increase in tissue potassium. Although massive calcium accumulation develops when irreversibly injured tissue is reperfused, no calcium overload was detected during early reperfusion of reversibly injured myocytes. Reperfusion for 3 minutes exaggerated the mitochondrial swelling induced by 15 minutes of ischemia but after 20 minutes of reperfusion, myocardial ultrastructure was essentially normal except for rare swollen, or disrupted, mitochondria. Thus, the cellular abnormalities associated with brief periods of ischemia persist for variable periods of time after reperfusion of reversibly injured myocytes. First: although adenine nucleotide repletion occurs very slowly, the adenylate charge was restored after 3 minutes, indicating rapid resumption of mitochondrial adenosine triphosphate production. Second: calcium overload was not detected, but myocardial edema and increased potassium persisted throughout the 20 minutes of reperfusion. Third: the ultrastructural consequences of ischemia were nearly reversed after 20 minutes of reperfusion.

Adenine Nucleotides↗
PubMed1985

Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models.

The Animal Models for Protecting Ischemic Myocardium Study was undertaken for the purpose of developing reproducible animal models that could be used to assess interventions designed to limit infarct size. This paper describes the results obtained in an unconscious dog model and in a conscious dog model, developed in three participating laboratories. The unconscious dog model, involving reperfusion after 3 hours of ischemia in open-chest dogs, was intended to determine whether therapy followed by early reperfusion would limit infarct size more than reperfusion alone. The conscious dog model used chronically instrumented dogs and permanent coronary occlusion to better mimic myocardial infarction in man. In both models, the proximal circumflex artery was occluded, and the primary experimental endpoint was infarct size, as measured by histological techniques 3 days after the initial occlusion. Infarct size was analyzed in relation to baseline variables including the anatomic area at risk, collateral blood flow to the subepicardial zone of ischemia and hemodynamic determinants of myocardial metabolic demand. Most of the variation in infarct size in control dogs could be related to variation in the area at risk, collateral blood flow, and rate pressure product. Using multivariate analysis and groups of 15 dogs, an intervention that limited infarct size by 10-13% of the area at risk would have been detected 50% of the time. Larger treatment effects would be detected more readily, and smaller effects often would be missed, unless group sizes were larger. Two drugs, verapamil and ibuprofen, were evaluated in both models, with experimental group sizes averaging 13 and 20 dogs, in the unconscious and conscious models, respectively. Three of 15 verapamil-treated dogs in the unconscious model study had much smaller infarcts than expected from baseline parameters. With these exceptions, neither drug limited infarct size in either model.

Anesthesia↗
PubMed1985

Volume regulation and plasma membrane injury in aerobic, anaerobic, and ischemic myocardium in vitro. Effects of osmotic cell swelling on plasma membrane integrity.

The relationship between cell swelling and plasma membrane disruption has been evaluated in thin myocardial slices incubated in oxygenated or anoxic Krebs-Ringer phosphate media. Electron microscopy and measurements of inulin-diffusible space were used to monitor plasma membrane integrity. Inulin is excluded from the intracellular space of intact cells; therefore, an increase in tissue inulin content is an excellent marker of loss of plasma membrane integrity. Cell volume was increased during exposure of aerobic slices to hypotonic media, but the inulin-diffusible space was not increased and electron micrographs showed no detectable plasma membrane alterations. Likewise, during prolonged anoxic isotonic incubation, no evidence of plasma membrane damage was observed. Incubation in anoxic hypotonic media for 60 minutes resulted in a larger increase in cell volume than under aerobic conditions, but plasma membrane integrity was maintained. Extended anoxic hypotonic incubation (300 minutes) produced no further change in tissue water, but the inulin-diffusible space was increased and electron micrographs revealed breaks in the plasma membranes primarily in association with large subsarcolemmal blebs. Likewise, myocardial slices incubated in isotonic anoxic media for 240 minutes and hypotonic anoxic media for 60 minutes had an increased inulin-diffusible space and the ultrastructural appearance was similar. This ultrastructural appearance is indistinguishable from that observed in myocytes lethally injured by ischemia. Measurements of tissue osmolarity during total ischemia showed that osmotically induced cell swelling could occur in ischemic myocardium prior to the onset of plasma membrane disruption. Our results indicate that cell swelling per se is incapable of rupturing plasma membranes; however, after prolonged periods of energy deficiency, the plasma membrane or its cytoskeletal scaffold become injured, which allows the membrane to rupture if the cell is swollen, as might occur during ischemia or reperfusion.

Aerobiosis↗
PubMed1984

Tetralogy of Fallot and coarctation of the aorta: successful repair in an infant.

A 4 1/2-month-old infant was referred to our center with the rare combination of tetralogy of Fallot and coarctation of the aorta. Despite the presence of severe right ventricular outflow obstruction, the infant was virtually acyanotic because of the systemic afterload associated with the coarctation. She had marked systemic hypertension. The embryological and therapeutic implications of this child's defects are discussed.

Aortic Coarctation↗
PubMed1984

Relationship between lysophospholipid accumulation and plasma membrane injury during total in vitro ischemia in dog heart.

The relationship between alterations in tissue phospholipid composition and disruption of the plasma membrane during ischemia in dog heart was examined using a homogeneous in vitro model of total ischemia. This preparation was known to be associated with signs of membrane damage and was ideal for quantitation of phospholipid changes in ischemia because the weight of the tissue is unaffected by the duration of ischemia and because there is no collateral flow to remove the endproducts of phospholipid degradation. Measurements of phospholipid phosphate per gram of tissue confirmed that recovery of phospholipids and their degradation products was essentially complete in all samples including a sample taken after 24 h ischemia. The results showed that lysophospholipids gradually accumulated in the ischemic tissue; after 24 h in vitro ischemia, they comprised 12% of the total tissue phospholipids. Discontinuities of the plasma membrane were detected ultrastructurally in myocardium subjected to 150 min total ischemia, while under the same conditions, the lysophospholipid content amounted to less than 1% of the total tissue phospholipids. Phospholipid degradation was not limited by calcium availability since the rate of lysolipid production was not enhanced by incubation of myocardial tissue in a medium containing 1.25 mM calcium despite ultrastructural evidence of antecedent plasma membrane disruption. These data indicate that lysophospholipids accumulate in ischemic myocardium in the absence of collateral flow or inflammatory cell infiltration but that lysophospholipid accumulation occurs slowly and does not appear to be the dominant mechanism of plasma membrane fragmentation.

Animals↗
PubMed1984

Verapamil in two reperfusion models of myocardial infarction. Temporary protection of severely ischemic myocardium without limitation of ultimate infarct size.

The ability of verapamil to protect severely ischemic myocardium was assessed in dogs using 40 minutes of temporary coronary occlusion. Reperfusion was established for 4 days after which infarcts were sized histologically. Untreated dogs developed subendocardial infarcts (the more moderately ischemic subepicardial region being salvaged by reperfusion). Pretreatment with verapamil reduced the size of these subendocardial infarcts from 34 +/- 8 to 8 +/- 3% of the ischemic circumflex vascular bed at risk (identified by postmortem perfusion of the previously occluded and unoccluded arteries with different dyes). Thus, verapamil prevented cell death in the severely ischemic subendocardial region for the 40-minute test period. In a second study to establish whether verapamil could delay cell death for a longer period of time in the less severely ischemic subepicardial region, a 3-hour period of coronary occlusion was used. This period of occlusion caused infarcts averaging 60 +/- 6% of the ischemic area at risk in untreated dogs. Dogs treated with verapamil 15 minutes postocclusion and throughout the remaining 165 minutes of the 3-hour test period had no limitation of infarct size (53 +/- 3% of the area at risk). In this 3-hour study, the effect of variation in collateral blood flow on infarct size was evaluated by plotting infarct size versus subepicardial collateral flow. Verapamil neither improved collateral flow nor altered the relationship between infarct size and baseline collateral flow. Thus, pretreatment with verapamil prevented necrosis of severely ischemic myocytes, when reperfusion was established at 40 minutes, but failed to prevent necrosis of moderately ischemic myocardium and thus failed to limit infarct size when the period of coronary occlusion was prolonged to 3 hours and treatment was started 15 minutes after the onset of ischemia.

Animals↗
PubMed1983

Pathobiology of acute myocardial ischemia: metabolic, functional and ultrastructural studies.

Acute myocardial ischemia induced by coronary occlusion in dogs is most severe in the subendocardial region, whereas more collateral blood flow is often present in the subepicardial region. Initially, all ischemic myocytes are reversibly injured, but beginning at 15 to 20 minutes after the onset, and continuing for 3 to 6 hours, there is a wave front of cell death from the subendocardial region to the less ischemic subepicardial region, such that by 6 hours, the final transmural extent of the infarct is established. Thus, ischemic myocardium cannot be salvaged by reperfusion after greater than or equal to 6 hours of coronary occlusion in open-chest anesthetized dogs. In the severely ischemic subendocardial region, most of the creatine phosphate is lost within the first 3 minutes of ischemia in vivo, and adenosine triphosphate (ATP) is depleted to 35% of control by 15 minutes (when cellular injury is still reversible), and to less than 10% of control at 40 minutes (when injury is irreversible). Tissue ATP content and other indexes of subcellular damage have also been compared after different periods of ischemia using a model of total myocardial ischemia in vitro. As long as the ATP of the tissue was not depleted below 5 mumols/g dry weight, incubated slices of injured myocardium resynthesized high-energy phosphates and excluded inulin. However, lower tissue ATP was 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 only after the tissue ATP decreased to less than 2.0 mumols/g of dry weight. Thus, marked ATP depletion is associated with the onset of structural and functional indexes of irreversible injury. However, whether irreversibility is caused by the marked ATP depletion or by other concomitant metabolic consequences of ischemia is not known. Myocardial ischemic cellular injury is reversible despite depletion of 70% of the control ATP. Nevertheless, when myocyte injury is reversible, there is slow repletion of adenine nucleotides. This slow metabolic recovery may explain the delayed recovery of contractile function observed after reperfusion of ischemic myocardium.

Adenine Nucleotides↗