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Biomedical subjects

R B Jennings

Publications and source records attributed to R B Jennings.

At least 55 records · Page 3Linked to original sources
PubMed1989

Total ischemia III: Effect of inhibition of anaerobic glycolysis.

The effect of inhibition of glycolysis with sodium iodoacetate (IAA) on the changes induced by total ischemia was studied in canine left ventricle. Hearts were excised from phenobarbital anesthetized dogs and the circumflex (LCC) and anterior descending (LAD) branches of the left coronary artery were perfused in order to expose the LCC region to 48 mumol of IAA (about 1.5 mumol/g wet wt). The LAD regions of the same hearts served as untreated control myocardium. Hearts then were subjected to total ischemia in vitro at 37 degrees C. Metabolites, ultrastructure, and the capacity of thin incubated slices of heart to maintain volume and ion gradients were studied in the control and IAA-treated regions. Depletion of ATP to levels of 3-4% of control occurred in only 4-5 min of ischemia in the IAA-treated myocardium, but similar depletion required 90 min of total ischemia in untreated myocardium. These low levels of ATP were associated with marked contracture-rigor. Depletion of ATP in the IAA treated region was accompanied by a marked increase in adenosine levels in the tissue at the onset of rigor (approximately 5 min); at this time, as much as 50% of the adenine nucleotide pool (sigma Ad) was in the form of adenosine. In contrast, inosine was the predominant catabolite at 5 min in control myocardium, and only composed 16% of the sigma Ad pool. Thus, pretreatment with IAA produced an enormous acceleration in the rate at which the sigma Ad pool was consumed in totally ischemic myocardium. Lactate, the principal glycolytic intermediate which accumulates in totally ischemic tissue, was not formed in the IAA-treated heart. Moreover, IAA treatment did not accelerate the rate at which ultrastructural evidence of lethal injury developed in the poisoned myocytes. Thus, in a setting in which lactate accumulation did not occur, totally ischemic myocytes tolerated a very low level of high energy phosphate for a longer period of time than did untreated tissue before ultrastructural signs of cell death developed. The results indicate that marked ATP depletion, pe se, does not necessarily cause prompt sarcolemmal disruption.

Adenine Nucleotides↗
PubMed1989

The correlation of mononuclear cell phenotype in endomyocardial biopsies with clinical history and cardiac dysfunction.

Endomyocardial biopsy specimens from 96 patients with unexplained congestive heart failure or dysrhythmia were evaluated by standard histologic techniques and by direct immunofluorescence and immunoperoxidase cell marker analysis for mononuclear cell infiltration. Control specimens derived from normal autopsy hearts (n = 8) and autopsy hearts with severe coronary artery disease (n = 9) were analyzed in a similar fashion. The results were correlated with functional data obtained from cardiac catheterizations as well as the clinical history. The objectives of the study were to assess the sensitivity and specificity of immunoperoxidase identification of lymphocytes for the diagnosis of myocarditis and to correlate clinical parameters such as degree of cardiac dysfunction and symptom duration with the extent of inflammatory changes. No control biopsies (neither normal nor ischemic) had a T-cell concentration of one or more cells per high-power field (HPF:200X), whereas 32% of the study cases had more than one T-cell per HPF. Heavy T-cell infiltration (greater than or equal to 3 per HPF) was present in 7% of the study cases and occurred most commonly when the symptoms were of recent onset. The results demonstrate that lymphocytes are not present (less than 1 per HPF) in normal myocardium, in viable myocardium from hearts with generalized coronary artery disease, and in most endomyocardial biopsies (68%) from patients with unexplained heart failure or dysrhythmia. Thus, lymphocyte infiltration is not a nonspecific response to cardiac dysfunction. Immunoperoxidase identification of lymphocytes provides a quantitative assessment of inflammatory cell infiltration that is useful in the detection of myocarditis.

Adolescent↗
PubMed1989

Effect of a critical coronary stenosis on myocardial neutrophil accumulation during ischemia and early reperfusion in dogs.

In many experimental models of ischemia and reperfusion, reperfusion is performed abruptly, allowing full reactive hyperemia to occur. In the clinical setting, however, reperfusion after thrombolysis is often limited by residual stenosis. Some experimental models attempt to mimic this situation with a "critical stenosis" (defined as a coronary constriction sufficient to abolish reactive hyperemia without altering baseline flow). The purpose of this study was to determine whether preventing reactive hyperemia during the initial phase of reperfusion would modify the transmural distribution of myocardial blood flow or the myocardial accumulation of polymorphonuclear leukocytes (PMNs). The left circumflex artery was occluded for 90 minutes and then reperfused for 60 minutes in anesthetized, open-chest dogs. Autologous PMNs were isolated, labeled with 111In, and reinjected 1 hour before coronary occlusion. 125I-labeled albumin was injected simultaneously to correct for 111In associated with plasma proteins and to permit calculation of the number of PMNs in the inner, middle, and outer thirds of nonischemic and ischemic-reperfused tissue. The presence of a critical stenosis abolished reactive hyperemia during the first 5 minutes of reperfusion, but did not substantially affect blood flow measured after 55 minutes of reperfusion. In both groups, there was a significant accumulation of PMNs in all layers of the ischemic-reperfused bed compared with the nonischemic bed, and the magnitude of this PMN accumulation was not altered by the presence of a critical stenosis. Moreover, infarct size, estimated by triphenyl tetrazolium chloride (TTC) loss after 60 minutes of reperfusion, was not affected by the presence of a critical stenosis. Thus, the presence of a critical stenosis abolished the hyperemic blood flow after reperfusion but did not influence the early PMN response to ischemia and reperfusion or the early loss of TTC staining.

Animals↗
PubMed1989

Alterations to subplasmalemmal leptomeres in adult canine myocytes during total in vitro ischemia.

Published evidence suggests that ischemia-induced cell swelling renders myocytes vulnerable to plasmalemmal disruption and consequent cell death. Alterations to the myocyte cytoskeleton may be involved in the pathogenesis of this plasmalemmal injury. One putative cytoskeletal structure in cardiac muscle that has received little consideration is the subplasmalemmal network of periodic densities with linking microfilaments termed leptomeres or leptofibrils. We demonstrate these structures in dog heart papillary muscle and describe the improvement in their definition brought about by tissue fixation at 37 degrees C in 2% glutaraldehyde with addition of 0.05 M lysine-HCl, followed by brief postfixation with osmium tetroxide. Alterations to leptomeres during ischemic injury were examined in myocardium subjected to total in vitro ischemia for 30-180 min at 37 degrees C. Leptomeres showed little morphological alteration during the first 90-120 min, after which leptomere periodic densities (striae) increased in size, from 10-20 to 50-80 nm, and were more densely stained. The leptomeres eventually (150-180 minutes) lose definition. The course of these alterations coincided with the appearance of ultrastructural evidence of irreversible ischemic injury to the myocytes.

Animals↗
PubMed1988

The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion.

Free radicals such as superoxide (.O2-) produced by xanthine oxidase might cause cell death during reperfusion after myocardial ischemia. The effect of the xanthine oxidase inhibitor allopurinol on infarct size in ischemia-reperfusion models has been variable, possibly because of differences in treatment duration. Adequate inhibition of xanthine oxidase may require a sufficient pretreatment period to permit conversion of allopurinol to oxypurinol, the actual inhibitor of superoxide production. To test more definitively whether xanthine oxidase-derived free radicals cause cell death during reperfusion, the effect of oxypurinol on infarct size was evaluated in an ischemia-reperfusion model. Open chest dogs underwent 40 min of circumflex coronary artery occlusion followed by reperfusion for 4 days. Twelve dogs were treated with oxypurinol (10 mg/kg body weight intravenously 10 min before occlusion and 10 mg/kg intravenously 10 min before reperfusion) and 11 control dogs received drug vehicle alone (pH 10 normal saline solution). Nine control dogs from a concurrent study also were included. Infarct size was measured histologically and analyzed with respect to its major baseline predictors, including anatomic area at risk and collateral blood flow (measured with radioactive microspheres). Infarct size as a percent of the area at risk averaged 23.8 +/- 2.7% (mean +/- SEM) in the oxypurinol group (n = 10) and 23.1 +/- 4.2% in the control group (n = 17) (p = NS). Collateral blood flow to the inner two thirds of the ischemic wall averaged 0.08 +/- 0.01 ml/min per g in the oxypurinol group and 0.09 +/- 0.02 ml/min per g in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Transatrial repair of double-chambered right ventricle.

Double-chambered right ventricles (DCRVCs) traditionally have been repaired via a right ventriculotomy. We describe the cases of 8 children (aged 7 months to 6 years; weight, 6.3 to 21.5 kg), who underwent repair of DCRV via a right atriotomy. Six patients had ventricular septal defects. Peak systolic gradients in the right ventricular outflow tract were 26 to 135 mm Hg. The QP/QS were 1.1 to 2.5. Cardiopulmonary bypass times were 52 to 89 min (mean, 65.5 min) with aortic cross-clamp times of 20 to 56 min (mean, 39 min). Mean intraoperative gradients following repair were 5.8 mm Hg. Three patients had transient postoperative atrioventricular block requiring temporary pacing. Two patients required minimal inotropic support (dopamine, 2.5 to 5 micrograms/kg/min). The children have all been asymptomatic after hospitalization with follow-up times of 5 months to 4.5 years. No patient requires cardiac medications or has significant, persistent dysrhythmias; however, 1 patient required reoperation. Transatrial repair of DCRV allows excellent operative anatomical visualization and should be considered as an alternative to the transventricular approach in patients with this congenital heart defect.

Cardiac Surgical Procedures↗
PubMed1988

Complete global myocardial ischemia in dogs.

Complete global myocardial ischemia or zero coronary arterial flow in dogs results in a series of well-defined changes which begin when the myocardium converts from aerobic to anaerobic metabolism. These processes continue until the myocardium dies. The products of anaerobic metabolism, chiefly glycolytic intermediates, inorganic phosphate, H+, and creatine, are produced intracellularly and accumulate in the tissue. Because the demand for high-energy phosphates (HEP) in the tissue exceeds the supply available from anaerobic glycolysis and HEP reserves, net ATP level declines, approaching zero after 100 min of ischemia at 37 degrees C. At this time, the changes in totally ischemic tissue in vitro are equivalent to those seen in myocytes irreversibly injured by severe ischemia in vivo. During reoxygenation after total ischemia, the resumption of effective contractile activity depends partly on the metabolic changes and degree of myocyte injury sustained during ischemia.

Animals↗
PubMed1988

Myocardial neutrophil accumulation during reperfusion after reversible or irreversible ischemic injury.

Recent studies suggest that polymorphonuclear leukocytes (PMNs) may cause additional myocyte injury during reperfusion of ischemic myocardium. The present study was done to investigate whether PMNs accumulate in myocardium during early reperfusion after reversible or irreversible ischemic injury. Open-chest anesthetized dogs underwent circumflex coronary occlusions for 12 min (n = 5), 40 min (n = 8), or 90 min (n = 8), followed by 1 h of reperfusion. Autologous PMNs were radiolabeled with 111In and reinjected to quantitate myocardial PMN influx during reflow. 125I-labeled albumin was injected simultaneously to correct for 111In associated with plasma proteins in myocardial tissue. The number of PMNs was determined in the inner, middle, and outer one-third of nonischemic and ischemic-reperfused myocardium. In the 12-min group, 40% fewer PMNs were present in the reperfused than in the nonischemic control tissue. In contrast, in both the 40- and 90-min groups, PMN accumulation was two- to sixfold greater in the ischemic-reperfused than nonischemic myocardium, with a transmural gradient of PMN influx increasing from the outer to inner layers. Collateral blood flow, measured with radioactive microspheres, was not significantly different among the three groups. The failure of PMNs to accumulate during reperfusion after 12 min of ischemia does not support the hypothesis that PMNs contribute to postischemic dysfunction of reversibly injured myocytes. Whether PMNs caused cell death during early reperfusion after longer ischemic episodes remains unknown; however, the rapidity of PMN accumulation in the zones of predicted infarction is consistent with this possibility.

Animals↗
PubMed1988

Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs.

It has been postulated that oxygen-centered free radicals are produced in significant quantities upon reperfusion of ischemic myocardium and could cause the death of myocytes that are still reversibly injured at the end of ischemia ("reperfusion injury"). However, we have shown previously that anti-free radical therapies including superoxide dismutase (SOD) and inhibitors of xanthine oxidase did not limit infarct size after 40 minutes of ischemia and 4 days of reperfusion in dogs. To test whether 40 minutes of ischemia is too brief a period to produce the prerequisite conditions for free radical-mediated necrosis upon reperfusion, we studied infarcts produced by 90 minutes of ischemia followed by reperfusion. Dogs in an SOD-catalase group received a 60-minute infusion of SOD (15,000 units/kg) and catalase (55,000 units/kg) beginning 25 minutes before and ending 35 minutes after reperfusion. A second group of dogs received a single injection of the xanthine oxidase inhibitor oxypurinol (20 mg/kg) 25 minutes before reperfusion. Infarct size was assessed histologically relative to the size of the area at risk and to collateral blood flow to the ischemic region. Infarct size as a percentage of the area at risk was similar in the control group (40.7 +/- 5.5%, n = 11), the SOD-catalase group (38.0 +/- 6.4%; n = 8), and the oxypurinol-treated group (41.4 +/- 6.1%; n = 7) [p = not significant (NS) by analysis of variance]. In controls, there was an inverse relation between infarct size and collateral blood flow; neither of the treatments altered this relation (p = NS by analysis of covariance).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Cytoskeletal injury and subsarcolemmal bleb formation in dog heart during in vitro total ischemia.

In previous studies a two-step hypothesis explaining the mechanism of lethal ischemic injury to cardiac myocytes has been advanced. It proposes that damage to the myocyte cytoskeleton precedes, and predisposes the cell to, mechanical injury induced by cell swelling or by ischemic contracture. This study quantitated the prevalence of breakage of the major cytoskeletal attachment between the plasmalemma and peripheral myofibers as a function of the duration (0-180 minutes) of in vitro total ischemia in dog heart papillary muscle. Breakages of Z-band, plasmalemmal attachment complexes were few before 120 minutes of ischemia, but thereafter became more prevalent; the transition between the initial rate of appearance of the breaks and the later fast rates coincided with the appearance of severe cell swelling, ischemic contracture, and ultrastructural criteria of irreversible ischemic injury. Z-band, plasmalemmal attachment complex breakage and cell swelling resulted in formation of subsarcolemmal blebs. Two major bleb types have been discerned on ultrastructural appearance using as the criteria the preservation of integrity of the plasma-lemma and subplasmalemmal leptomeres. The identification of two types of blebs suggests two independent mechanisms of injury, the first directed at Z-band attachments, and the second at the cytoskeletal structures of A- and I-band regions of the plasmalemma.

Animals↗
PubMed1988

Myocyte swelling and plasmalemmal integrity during early experimental myocardial ischemia in vivo.

Using scanning and transmission electron microscopy, the structure of myocytes early in the phase of irreversible injury induced by 40 minutes of severe regional ischemia has been investigated, paying particular attention to the effects of cell swelling on the SEM appearance of the myocytes. Swollen myocytes showed an increased space beneath the plasmalemma and between organelles. True subsarcolemmal blebs were not seen and the attachment complexes between the Z-band and the underlying myofibrils remained intact. The proportion of the PS face of the plasmalemma which appeared "en face" (0.70%, SD:1.22 vs 5.01%, SD:3.72) in freeze-fracture faces of ischemic tissue was increased significantly. The increase may be due to swelling of the cell in the subplasmalemmal space or may be mediated through structurally unapparent alterations in the cytoskeleton. The PS face showed frequent longitudinal shifts in the alignment of Z band - plasmalemmal attachment between adjacent myofibers. T-tubule ostia, caveolae and junctional SR were demonstrable on the PS face. With standard preparative methods and instrumentation, no discrete fibrillar network associated with Z band attachment or subjacent to the plasmalemma was detected and there was no direct structural evidence of cytoskeletal alteration as a result of ischemic injury. Osmium-ligand preparation of tissue samples resulted in less damage induced by the electron beam, but did not allow significantly better resolution.

Animals↗
PubMed1987

Failure of superoxide dismutase to limit size of myocardial infarction after 40 minutes of ischemia and 4 days of reperfusion in dogs.

Reactive oxygen species such as the superoxide anion (.O2-) have recently been implicated as important agents involved in causing cell death in the setting of myocardial ischemia and reperfusion. When superoxide anion is involved in ischemic injury the administration of superoxide dismutase (SOD) may limit infarct size by reducing the level of superoxide anions in the myocardium. The study described herein was done to determine whether SOD could limit myocardial infarct size when infarcts were produced in dogs by a 40 min occlusion of the circumflex coronary artery followed by 4 days of reperfusion. The animals in the SOD treatment group received a 1 hr intra-atrial infusion of SOD, at a rate of 250 U/kg/min starting 15 min after occlusion and ending 35 min after reperfusion; control dogs received a saline infusion over the same time frame. Infarct size was determined histologically and expressed as a percentage of the anatomic area at risk (AAR). Infarct size was similar in the two groups, averaging 26.2 +/- 2.5% in the control group (n = 10) and 21.1 +/- 4.8% in the SOD group (n = 11) (p = .40). Hemodynamic variables were not statistically different in the two groups during the occlusion. The transmural mean collateral blood flow at 10 min into the 40 min occlusion was 0.13 +/- 0.02 ml/min/g in the controls and 0.17 +/- 0.03 ml/min/g in the SOD group (p = NS); moreover, SOD did not alter collateral blood flow. In control dogs, infarct size was inversely related to collateral blood flow; analysis of covariance showed that SOD did not shift this relationship. Thus, SOD did not limit infarct size in this study. The results of the current study are consistent with our previous study in which allopurinol, a xanthine oxidase inhibitor, did not limit infarct size in this same experimental preparation. The results suggest that superoxide anions that are accessible to the infused SOD are not a major cause of myocyte death caused by 40 min of severe ischemia followed by reperfusion.

Animals↗
PubMed1987

Cytoskeletal damage during myocardial ischemia: changes in vinculin immunofluorescence staining during total in vitro ischemia in canine heart.

The role of cytoskeletal damage in the disruption of the plasma membrane observed during myocardial ischemia has been studied using antibodies to vinculin to identify changes in the distribution of this membrane associated cytoskeletal protein. Vinculin is a component of the cytoskeletal attachment complex between the plasma membrane and the Z-line of the underlying myofibrils. The effects of varying periods of total ischemia on the localization of vinculin were assessed by immunofluorescence and evidence of membrane disruption was evaluated by electron microscopy. Thin tissue slices prepared from the ischemic tissue were incubated in oxygenated Krebs-Ringer phosphate buffer at 37 degrees C to assess inulin permeability, ultrastructure, and any changes in the distribution of vinculin associated with incubation. The previously reported costameric pattern of vinculin staining was observed in longitudinal sections of control myocardium, myocardium subjected to 60 minutes of total ischemia, and myocardium subjected to 60 minutes of ischemia followed by 60 minutes of incubation in oxygenated media. Electron microscopy and inulin permeability measurements confirmed that plasma membrane integrity was preserved under these conditions. However, when the duration of total ischemia was extended to 120 minutes or longer, there was a progressive loss of vinculin staining along the lateral margin of myocytes. This change correlates with the appearance of subsarcolemmal blebs and breaks in the plasma membranes observed by electron microscopy and confirmed by the increase in inulin permeability observed in tissue slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗