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Query: UNIPROT:P06889 (Mol)
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In a previous study, we demonstrated a significant release of adenosine, inosine and hypoxanthine during hypoxia and subsequent reoxygenation. The present study was designed to determine whether or not exogenous adenosine, inosine and hypoxanthine are beneficial for the recovery of hypoxia-induced loss of cardiac contractile force. Hearts were perfused for 20 min under hypoxic conditions, followed by 45 min-perfusion under reoxygenated conditions, and changes in contractile force, resting tension and metabolic parameters of the perfused heart were examined. When either adenosine, inosine or hypoxanthine were exogenously infused during hypoxia at the rate of 3 mumol/min, remarkable recovery (61 to 68%) of cardiac contractile force was observed upon reoxygenation. The recovery was accompanied by a significant restoration of myocardial ATP (90 to 100%) and CP contents (80 to 86%), suggesting that exogenous metabolites are utilized for the restoration of myocardial ATP during reoxygenation, which may lead to a beneficial recovery of hypoxia-induced loss of cardiac contractile force upon reoxygenation. Infusion of exogenous metabolites also resulted in an almost complete inhibition of hypoxia- and reoxygenation-induced release of creatine phosphokinase from the perfused heart as well as a significant depression of hypoxia-induced calcium accumulation in the cardiac tissue. Since these phenomena are considered to represent increases in cell membrane permeability, protection of the myocardium against hypoxia- and reoxygenation-induced changes in cell membrane permeability may be an alternative mechanism for the beneficial effect of adenosine, inosine and hypoxanthine on the hypoxic myocardium.
J Mol Cell Cardiol 1988 Mar
PMID:Adenine nucleotide metabolites are beneficial for recovery of cardiac contractile force after hypoxia. 339 53

The systematic investigation of the genesis and control of arrhythmias during ischemia and reperfusion requires a reproducible preparation in which arrhythmias can be induced with relative ease. The requirements for appropriate statistical analysis often requires that large numbers of animals be studied and hence cost becomes an important factor. The rat offers many advantages but is often criticized on the basis of its atypical action potential and a need exists for an alternative small animal model. The guinea-pig, because of its highly collateralized coronary circulation, cannot be used for the induction of regional ischemia and the rabbit is often dismissed on the grounds that it has a low incidence of arrhythmias. In the present study we have shown that if the perfusion conditions (duration of ischemia and extracellular potassium concentrations) are appropriately selected then the rabbit heart exhibits a high and reproducible susceptibility to reperfusion-induced arrhythmias. Hearts (n = 10 in each group) were subjected to 20 min of regional ischemia induced by coronary artery ligation, the potassium concentration of the perfusate being 2.50, 2.75, 3.00, 3.25, 3.50 or 4.38 mM. A bell-shaped relationship was demonstrated with an optimum susceptibility at 3.00 mM where 60% of the hearts exhibited reperfusion-induced ventricular fibrillation and 80% of the hearts exhibited ventricular tachycardia. With concentration of potassium above 3.00 mM there was a progressive decline in susceptibility (only one out of ten hearts fibrillated when potassium was 4.38 mM). With concentrations of potassium below 3.00 mM there was also a reduction in susceptibility to fibrillation. Using an optimally arrhythmogenic concentration of 3.00 mM potassium, hearts (n = 10 in each group) were subjected to 10, 15, 20, 25, 30 or 40 min of regional ischemia followed by 5 min reperfusion. A bell-shaped time-susceptibility curve was obtained such that with increasing durations of ischemia from 20 to 30 min there was an increasing incidence of reperfusion-induced arrhythmias. Beyond this optimum (at which 60% exhibited reperfusion-induced ventricular fibrillation) there was a decline in the susceptibility of the hearts to fibrillation. Heart rate and coronary flow exhibited no consistent significant relationship with either potassium concentration or duration of regional ischemia. Studies of the time of onset and duration of reperfusion-induced arrhythmias showed that 90% of arrhythmias were initiated within the first 60 s of reperfusion but that the duration was highly variable.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1988 Mar
PMID:Reperfusion-induced arrhythmias in the isolated rabbit heart: characterization of the influence of the duration of regional ischemia and the extracellular potassium concentration. 339 54

Using the isolated perfused rat heart with regional ischemia and reperfusion, we have two antiarrhythmic interventions (the spin trap agent PBN [N-tert-butyl-alpha-phenylnitrone] and perfusate calcium reduction), administered just before reperfusion, to investigate mechanisms determining the vulnerability of the heart to reperfusion-induced ventricular fibrillation. Hearts were subjected to regional ischemia (5, 10, 20, 30 or 40 min) followed by reperfusion. Four groups were studied for each ischemic time: (i) control hearts with no antiarrhythmic intervention; (ii) hearts perfused with PBN (30 mumol/l) during the final 1 min of ischemia and throughout reperfusion, (iii) hearts perfused with low-calcium buffer (0.4 mmol/l) during the final 1 min of ischemia and throughout reperfusion and (iv) hearts perfused with PBN (30 mumol/l) and low-calcium (0.4 mmol/l) during the final 1 min of ischemia and throughout reperfusion. In control hearts, a bell-shaped time-vulnerability curve was obtained with 0, 91, 67, 33 and 17% of the hearts exhibiting irreversible fibrillation during reperfusion after 5, 10, 20, 30 and 40 min of ischemia, respectively. In the PBN group, the values were 8, 41 (P less than 0.05), 41, 33 and 8%, respectively. In the calcium reduction group the values were 17, 50, 8 (P less than 0.05), 8 and 0, respectively. Thus, PBN caused a significant reduction in reperfusion-induced ventricular fibrillation after 10 min of ischemia but had no significant effect with reperfusion after 20 min of ischemia. In contrast, calcium reduction had no significant effect after 10 min of ischemia but caused a significant reduction after 20 min of ischemia. When PBN treatment with calcium reduction were combined we obtained significant anti-arrhythmic effects after both 10 min (P less than 0.05) and 20 min (P less than 0.05) of ischemia. The additive effects of these two interventions, and the different ischemic-times after which they are most effective, has led us to propose that multiple triggers, each with different underlying mechanisms may be capable of initiating events which lead to ventricular fibrillation.
J Mol Cell Cardiol 1988 Mar
PMID:Free radicals and calcium: simultaneous interacting triggers as determinants of vulnerability to reperfusion-induced arrhythmias in the rat heart. 339 55

Impaired energy production has been proposed as one mechanism to explain the contractile abnormality in post-ischemic "stunned" myocardium. If energy production were impaired, administration of inotropic agents should result in a deterioration of cellular energy stores because of an inability of ATP synthesis to match the rate of increased utilization. In this study we correlated changes in myocardial high energy phosphates, measured by 31P-NMR spectroscopy, with changes in left ventricular function and energy requirement in buffer perfused rabbit hearts following ischemia and reperfusion, and during stimulation with isoproterenol. Hearts were stunned by 20 min of zero flow global ischemia at room temperature. After reperfusion, isovolumic developed pressure returned to 77.8 +/- 2.2% of baseline and ATP content was reduced to 80.9 +/- 4.1% of baseline. Isoproterenol (5 x 10(-8) M for 10 min) caused increases in developed pressure and rate-pressure product (to 134.1 +/- 12.6% and 195.0 +/- 21.4% of baseline, respectively) without a decrease in ATP or phosphocreatine (PCr) content (80.0 +/- 7.1% and 103.0 +/- 3.8% of preischemia, respectively), and without functional or metabolic deterioration of the hearts after discontinuation of the drug. Control hearts not subjected to ischemia showed similar functional and metabolic responses to isoproterenol. The phosphocreatine/inorganic phosphate (PCr/Pi) ratio, an index of the balance between energy production and utilization, was higher (not lower) than baseline in stunned hearts, thus confirming that energy production was not intrinsically impaired. Together these data indicate that despite reduced myocardial ATP content, mitochondrial function in stunned hearts is capable of sustaining a large increase in function and energetic requirements.
J Mol Cell Cardiol 1987 Oct
PMID:Preserved high energy phosphate metabolic reserve in globally "stunned" hearts despite reduction of basal ATP content and contractility. 343 54

Branched chain amino acids (BCAA) have been found to have a protective effect on the ischemic myocardium. Isolated rat hearts were perfused with phosphate-free Krebs-Henseleit (KH) solution with or without BCAA. A Latex balloon-tipped catheter was inserted into the left ventricle to measure intracavitary pressures. Hearts were subjected to 18 minutes of 'no flow' global ischemia and then reperfused for 30 mins at 37 degrees C. Metabolism of high energy phosphates during ischemia and recovery was studied by P-31 NMR. Intracellular pH was calculated from the chemical shift of Pi. Pressure recovery was better with KH + BCAA (89 +/- 16%) than with KH (41 +/- 26%) (P = 0.0001); dP/dt recovery was also improved with BCAA (84 +/- 19% vs 27 +/- 27% for KH) (P = 0.0003). After 18 mins of ischemia, ATP levels in the BCAA group were higher than in the KH perfused hearts (33 +/- 20 vs 17 +/- 10% of pre-ischemic value) (P = 0.02). No significant difference was found in the intracellular pH at the end of the ischemic period. Following reperfusion the recovery of pH was better in the BCAA group (7.09 +/- 0.06 vs 7.04 +/- 0.06) (P = 0.03). These results show that BCAA protect the heart from myocardial ischemic injury, decrease depletion of ATP during ischemia, and enhance post-ischemic hemodynamic function.
J Mol Cell Cardiol 1987 Oct
PMID:The protective effect of enriched branched chain amino acid formulation in the ischemic heart: a phosphorous-31 nuclear magnetic resonance study. 343 56

This study describes the effect of oxygen radicals on the ultrastructure of the isolated Langendorff-perfused rat heart. Oxygen radicals were enzymatically generated by xanthine oxidase (0.025 U/ml) and hypoxanthine (0.96 mM). Hearts were perfusion-fixed for electron microscopy and stereological technique was performed to obtain estimates of volume fractions (Vv) of different tissue components. Perfusion with oxygen radicals resulted in areas with severely damaged myocardial cells. These changes included swelling and cristolysis of mitochondria, disruption of filaments, development of intracellular edema and focal disruption of the sarcolemma. Stereological examination revealed few alterations after 5 min perfusion with oxygen radicals. After 10 min perfusion with oxygen radicals, however, the Vv (myocyte/myocardium) increased from 0.542 +/- 0.042 (mean +/- S.D.) to 0.663 +/- 0.144, and this paralleled the development of Vv (cellular edema/myocyte) being 0.047 +/- 0.028. Vv (capillary wall/capillary) increased from 0.215 +/- 0.046 to 0.411 +/- 0.123 indicating endothelial swelling. Although the mitochondria appeared swollen, Vv (mitochondria/myocyte) remained constant. The effect of a 35 min recovery period on the ultrastructure was minor. The application of SOD and catalase together with xanthine oxidase and hypoxanthine reduced the observed changes significantly, thus proving the participation of oxygen radicals. This study confirms that oxygen radicals can induce major alterations in myocardial ultrastructure.
J Mol Cell Cardiol 1987 Apr
PMID:Ultrastructural changes induced in the isolated rat heart by enzymatically generated oxygen radicals. 361 20

Two fatty acid blocking agents, oxfenicine (33 mg/kg) and 4-bromocrotonic acid (0.34 mg/kg/min for 70 min), were used to selectively adjust levels of long-chain acyl CoA and carnitine in aerobic and ischemic myocardium. The purpose of the study was to test whether the shift in these amphiphiles was associated with alterations of mechanical function in intact myocardium. The extracorporeally perfused swine heart preparation was used. Hearts were perfused at aerobic levels for 40 min following which flow to the anterior descending (LAD) circulation was reduced by 50% for the final 30 min of perfusion. All hearts were perfused with excess fatty acids to raise serum levels to 1.37 +/- 0.16 mumol/mol throughout the studies. Oxfenicine and 4-bromocrotonic acid affected a 20% (P less than 0.05 and P less than 0.05, respectively) further decline in 14CO2 production from labelled palmitate as compared with placebo hearts during regional ischemia. Accompanying this were downward shifts in acyl carnitine (-27 delta %, NS in aerobic tissue; -70 delta %, P less than 0.001 in ischemic tissue) and acyl CoA (-13 delta %, NS in aerobic tissue; -33 delta %, P less than 0.01 in ischemic tissue) for oxfenicine and upward shifts of acyl carnitine (+212 delta %, P less than 0.001 in aerobic tissue; -9 delta %, NS in ischemic tissue) and acyl CoA (+78 delta %, P less than 0.001 in aerobic tissue; +29 delta %, P less than 0.025 in ischemic tissue) for 4-bromocrotonic acid. These adjustments in amphiphiles were further associated with improved function (+55 delta % increase in max LV dP/dt, P less than 0.05) in oxfenicine-treated hearts and depressed function (+87 delta % increase in LVEDP, P less than 0.05) in 4-bromocrotonic acid-treated hearts. Thus, at comparable conditions of coronary flow, left ventricular pressure, and fatty acid availability and oxidation between treatments, depletion or build-up of CoA and carnitine esters as affected by selective inhibitors of fatty acid metabolism were causally linked to improved or impaired cardiac performance in intact hearts.
J Mol Cell Cardiol 1987 May
PMID:Effects of the fatty acid blocking agents, oxfenicine and 4-bromocrotonic acid, on performance in aerobic and ischemic myocardium. 362 84

Basal metabolism has been measured in isolated whole hearts from rabbits and compared with myothermic and polarographic measurements on isolated papillary muscles. Hearts were perfused at constant pressure (Langendorff method) using a modified Krebs-Henseleit solution (KH) with glucose as substrate. Higher levels of basal O2 consumption (MVO2) and coronary flow (CF) were observed when arrest was induced by calcium depletion (low Ca; 0.1 mM CaCl2, 10.0 mM KCl) rather than by potassium excess (high K; 30.0 mM KCl). The metabolic rate of high K arrested hearts was close to earlier myothermic estimates (J. Mol. Cell. Cardiol. 16: 953-962, 1984); polarographic values, however, were about twofold higher, and somewhat higher than the value obtained in low Ca arrested hearts. The addition of erythrocytes, albumin, or dextran significantly reduced CF but did not substantially alter basal MVO2. Basal metabolic rate was substrate- and O2 tension-dependent, and under all experimental conditions there was linear relationship between MVO2 and CF. Extrapolations to zero flow showed that the basal MVO2 values so obtained were similar in low Ca or high K and were not altered by the presence of erythrocytes. Our results show that there are several factors regulating basal metabolism.
 ...
PMID:Factors regulating basal metabolism of the isolated perfused rabbit heart. 371 71

The controversial issue of serum to milk transport of IgA in rodents was addressed in experiments that evaluated the molecular integrity and antigen-binding ability of the dimeric IgA (dIgA) recovered in the stomachs of rat and mouse pups suckling dams which had been administered homogeneous, dimeric M315 intravenously (i.v.). Four rat and three mice dams were i.v. administered affinity-purified, 125I-dIgA anti-DNP (M315) of which greater than 83% could bind DNP after iodination, and of which greater than 82% could be captured by solid phase anti-M315. Dams were given the labelled dIgA either 1-day or 8-days postpartum. Twenty-three hours after i.v. administration, the radioactivity of each pup, its stomach contents and an aliquot of serum were analyzed for total radioactivity, anti-DNP activity and for the molecular integrity of the recovered I-125. Data showed that 11-43% of 125I-activity given to the dam could be recovered from the stomach contents and sera of the pups after this time. Immunoassay revealed that less than 2% of the recovered radioactivity could bind DNP, i.e. a loss of 98% of functional antibody. It was calculated from ultracentrifugational analyses that less than 0.7% of the 125I-dIgA had been transported intact to the suckling neonates. Analyses of stomach milk and neonatal sera by sucrose density gradient ultracentrifugation revealed that almost all recovered radioactivity was in the form of low mol. wt fragments. Data fail to support the concept of an active mechanism for the transport of intact IgA from serum to milk in rodents during early or mid-lactation.
Mol Immunol 1986 Aug
PMID:Dimeric M315 is transported into mouse and rat milk in a degraded form. 379 27

This study was designed to compare the effects of the Ca2+ slow channel blocking agents verapamil (2 X 10(-6) M), diltiazem (7.5 X 10(-7) M), and buffer containing reduced Ca2+ content (0.95 mM) on myocardial ischemic injury. These treatments were equiactive, reducing cardiac function to 20% of the control value, and fully reversible in nonischemic, isolated, working rat hearts. Hearts which were reperfused (30 min) following 27 min of global ischemia recovered 17% of control cardiac function and had a markedly reduced ATP and creatine phosphate content and ATP/ADP ratio compared to nonischemic hearts. When verapamil, diltiazem, nifedipine, or low Ca2+ treatments were given before and during ischemia, equal improvement in cardiac function was observed upon reperfusion, and tissue ATP levels, creatine phosphate levels, and ATP/ADP ratio were significantly higher than in hearts which did not receive the treatments or which received the drug vehicle. Large increases in recovery of contractile function were observed with a partial preservation of ATP reserves. These treatments, which were equiactive in nonischemic hearts, provided equivalent preservation of cardiac function, ATP, and creatine phosphate in the reperfused ischemic hearts. When the ischemic period was increased to 33 min and the effective concentrations reduced to depress cardiac function to 40% of the control value (4.5 X 10(-7) M verapamil, 2.5 X 10(-6) M diltiazem, 3 X 10(-7) M Nifedipine, 1.25 mM Ca2+), equal improvement in cardiac function was again observed. Thus, major differences among these Ca2+ slow channel blockers or low Ca2+ treatment were not detected in this experimental system.
J Mol Cell Cardiol 1986 Mar
PMID:Comparison of the protective effects of verapamil, diltiazem, nifedipine, and buffer containing low calcium upon global myocardial ischemic injury. 395 95


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