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Query: UNIPROT:P06889 (Mol)
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Hearts from three species of fish with varying myoglobin content were perfused with stepwise changes in input perfusate PO2 from approximately 160 to 10 mmHg. Flow through the heart, rate of contraction, and afterload were kept constant. This standardized stroke volume and bulk flow of perfusate to the myocytes since these hearts are nourished by the fluid in the ventricular lumen. In some cases NaNO2 was added to the perfusion medium to decrease existing levels of functional myoglobin. Myoglobin-rich hearts were able to extract a constant amount of oxygen until perfusate PO2 had fallen below 80 mmHg. At this point oxygen uptake began to decline. These hearts consumed oxygen until input PO2 was 10 mmHg or less. When normoxic conditions were restored the myoglobin-rich hearts showed complete recovery. Performance was maintained at a constant level over the entire range of input PO2. Myoglobin-poor hearts and nitrite-treated hearts were unable to sustain constant levels of oxygen consumption in the face of a declining perfusate PO2. These hearts were unable to extract oxygen from the medium and failed at perfusate PO2's of 40 mmHg for naturally myoglobin-poor hearts and 30 mmHg for nitrite-treated hearts. Half-maximal oxygen consumptions were attained by myoglobin-rich hearts at lower input PO2's than either myoglobin-poor or nitrite-treated hearts. The impact of myoglobin in intact heart is apparent at relatively high extracellular PO2's (40-80 mmHg) in this model system.
J Mol Cell Cardiol 1990 Oct
PMID:Oxygen uptake by isolated perfused fish hearts with differing myoglobin concentrations under hypoxic conditions. 209 36

Acute adriamycin cardiotoxicity was studied in the isolated, perfused rat heart by 31P and 13C NMR spectroscopy at flow rates of 15 and 5 ml/min. Treated hearts received a total dose of 13.5 mg of adriamycin. 31P NMR spectra were collected at the beginning and end of each experiment, and cardiac function was recorded throughout. Hearts were perfused with [1-13C]glucose, and 13C NMR spectra were recorded in the presence and absence of the drug. At normal flow (15 ml/min), adriamycin caused a decline in cardiac function which was reversible when the drug was removed. There were no changes in high energy phosphate levels. The labeling of glutamate was unchanged in the presence of adriamycin; however, there was a slight increase in the labeling of lactate and alanine. At reduced flow (5 ml/min), control hearts exhibited a small decrease in ATP and phosphocreatine levels, and cardiac function was depressed. These changes were reversible when normal flow was restored. Nevertheless, adriamycin treatment at low flow caused an irreversible decline in function and in hydrolysis of ATP and phosphocreatine. At reduced flow, the control and drug-treated hearts showed similar labeling of the glutamate pool; however, there was significantly greater labeling of lactate and alanine during adriamycin treatment. These results indicate that adriamycin is more toxic under reduced flow conditions. Impairment of cardiac function by adriamycin without changes in glutamate labeling suggests that this drug alters the relationship between cardiac function and energy production.
J Mol Cell Cardiol 1990 Oct
PMID:The relationship between cardiac function and metabolism in acute adriamycin-treated perfused rat hearts studied by 31P and 13C NMR spectroscopy. 209 40

We have previously demonstrated that induction of the heat-shock response in rats results in improved recovery of isolated Langendorff-perfused rat hearts subjected to low-flow ischemia followed by reperfusion (Currie et al., 1988). The mechanisms underlying this protective effect of heat-shock are uncertain although the protection was associated with enhanced content of the antioxidant enzyme catalase but not superoxide dismutase or glutathione peroxidase (Currie et al., 1988). Various investigators have suggested the importance of improved energy metabolism in determining recovery following ischemia (Pasque and Wechsler, 1984; Haas et al., 1984; Devous and Lewandowski, 1987). We therefore examined, using a working rat heart model subjected to 10 or 15 min zero flow ischemia whether changes in energy metabolites could account for the protective effect of the heat-shock response. Hearts perfused 24 h after induction of heat-shock failed to demonstrate significant improvement of recovery following 10 min ischemia, however recovery was significantly enhanced in hearts reperfused after 15 min ischemia. Ischemia produced a depression in both ATP and creatine phosphate (CP) content whereas a moderate elevation in ADP and AMP and a marked increase in tissue lactate were evident. These changes were unaffected by prior heat-shock treatment. For both durations of ischemia tissue metabolites were determined during early (5 min) and late (30 min) reperfusion. Although partial recovery in high energy phosphates and a return of ADP, AMP and lactate to near-normal levels were evident, no differences in energy products were observed between hearts from normal or heat-shocked animals, in spite of significantly enhanced recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1990 Jun
PMID:Improved post-ischemic ventricular recovery in the absence of changes in energy metabolism in working rat hearts following heat-shock. 223 33

The rate of release of purines (adenosine, inosine, hypoxanthine, xanthine and uric acid) from isolated working rat hearts was measured and compared to tissue concentrations of high energy phosphate compounds. Hearts were subjected to different workloads, and perfusions were performed: with normal oxygen supply (group 1); with the addition of insulin to the standard perfusion buffer, which contained glucose as energy source (group 2); in hypoxic conditions (group 3). In each group purine release increased (P less than 0.01) at higher workload and was closely related to indices of mechanical performance such as cardiac output or minute work (r = 0.902 and 0.858 in group 1, r = 0.902 and 0.851 in group 2, r = 0.851 and 0.881 in group 3, P less than 0.001 in each case). Work had no effect on adenine nucleotides but produced a significant (P less than 0.01) reduction in phosphocreatine/creatine ratio. The comparison of different groups showed that at any level of heart performance purine release was higher (P less than 0.001) in group 3 vs. group 1, and lower (P less than 0.001) in group 2 vs. group 1. High energy phosphates were reduced in group 3 vs. group 1 but were unchanged in group 2 vs. group 1. We conclude that in the isolated heart purine release is directly related to the rate of energy consumption, and inversely related to the rate of energy production. Purine release provides a sensitive method to evaluate myocardial energy metabolism, which is more sensitive than measurement of high energy phosphates.
J Mol Cell Cardiol 1990 Jul
PMID:Purine release from isolated rat heart: a new approach to the study of energy metabolism. 223 46

In the present study we have examined the effect of the general anesthetic agent sodium pentobarbital (given i.p. to the intact animal) on the hemodynamic function of the isolated perfused heart and its response to treatments which affect calcium transsarcolemmal influx: extracellular calcium concentration and thyroid hormone. Perfused hearts (modified Langendorff system) isolated from anesthetized rats were found to respond differently to the two aforementioned effectors than hearts excised from non-anesthetized animals. Hearts of the two groups demonstrated a gradual increase in inotropic activity in response to step-wise increase in calcium concentration in the perfusion medium. However, cardiac contractility and the pattern of the response to the gradual increase in calcium concentration were different. At the lower Ca2+ concentrations of 0.5 and 1.0 mM, inotropic activity (left ventricular systolic pressure (LVP) and +dP/dt values) of hearts from anesthetized animals was significantly greater (P less than 0.05) than that of hearts from non-anesthetized animals: LVP values (mmHg, mean +/- S.E.M.) in hearts from anesthetized an non-anesthetized rats were: at 0.5 mM Ca2+, 19 +/- 3 and 9 +/- 2; and at 1.0 mM, 103 +/- 12 and 76 +/- 6, respectively. At the higher Ca2+ concentrations, hearts from anesthetized animals demonstrated maximal LVP at 1.75 mM calcium (139 +/- 9 mmHg), whereas the LVP values in hearts from non-anesthetized animals continued to increase throughout all the Ca2+ concentrations employed. A similar pattern of response was observed for +dP/dt values.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1990 Nov
PMID:Effect of anesthesia on cardiac function and response in the perfused rat heart. 228 88

The purpose of this study was to determine if the cardioprotective effect of adenosine on the ischemic myocardium is mediated by interaction with specific adenosine receptor subtypes. Isolated rat hearts perfused at constant flow were subjected to global normothermic (37 degrees C) ischemia and the time to onset of ischemic contracture (TOIC) was used as a marker of myocardial ischemic injury. Hearts treated with adenosine and R-phenylisopropyladenosine (PIA), an adenosine A1 receptor agonist, exhibited a significantly greater TOIC than control hearts (18.60 +/- 0.40 and 16.64 +/- 1.15 min, respectively vs 9.12 +/- 0.66 min), whereas phenylaminoadenosine, an adenosine A2 receptor agonist, had no effect on TOIC (11.73 +/- 0.87 min). BW A1433U, an adenosine receptor antagonist, blocked the effects of adenosine and PIA on ischemic contracture time, and BW A1433U did not alter the ability of nifedipine or propranolol to delay the onset of ischemic contracture, thus indicating the specificity of this compound for the adenosine receptor. PIA-treated hearts exhibited significantly greater ATP levels throughout the ischemic period compared to control hearts, whereas hearts treated with BW A1433U showed a rapid decline in ATP content. These results suggest that the beneficial effects of adenosine on the ischemic myocardium are mediated by interaction with adenosine A1 receptors, and that endogenously formed adenosine plays a role in attenuating myocardial ischemic damage.
J Mol Cell Cardiol 1990 Jan
PMID:Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. 232 32

Hepatitis B viral particles (HB-VP) were purified from sera of chronic hepatitis B surface antigen (HBsAg) positive carriers by consecutive isopycnic and rate-zonal sedimentation in sucrose gradients. Their immunological properties [HBsAg, hepatitis B core antigen (HBcAg) and hepatitis B e-antigen (HBeAg) activities] were examined by a radioimmunoassay based upon the classical "sandwich principle". A double antibody specificity radioimmunoassay (DAS-RIA) was then developed to determine whether envelope proteins (HBsAg) with binding activity for polymerized human serum albumin (pHSA-BA) were associated with core-specific antigenicities (HBc/HBeAg). An e-antigen activity cosedimenting with intact HB-VP (negative for HBcAg reactivity) was detected in association with HBsAg and receptors for pHSA. The presence of HBcAg-specific determinant(s) on HBeAg molecules was also indicated by DAS-RIA. So, we postulated that such hepatitis B virion (HBV) specific molecules are involved in immune complexes with anti-HBc as antibodies in sera of patients with chronic HBV infection. To define the significance of these molecular forms in HB-VP morphogenesis, we studied the effects of a mild treatment with a chaotropic salt, NaSCN, on HB-VP-rich fractions (DNA polymerase positive). A small mol. wt HBeAg derived from HB-VP by dissociating treatment was detected. We found that core-specific determinants (HBe/HBcAg) were bound to large surface proteins (HBsAg) with pHSA-BA and therefore probably contained the pre-S sequence. The selective release from HB-VP of such molecular forms, which could be a product of the major S-region transcript, suggests that they may be components of complete virions.
Mol Immunol 1985 Nov
PMID:Demonstration of a firm association between hepatitis B surface antigen proteins bearing polymerized human albumin binding sites and core-specific determinants in serum hepatitis B viral particles. 241 11

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.
J Mol Cell Cardiol 1989 Feb
PMID:Total ischemia III: Effect of inhibition of anaerobic glycolysis. 273 29

Left ventricular (LV) contractile function and pump function were depressed in isolated working hearts from rats treated with either guanidinopropionic acid (GPA), an inhibitor of creatine influx, or the anthracycline antibiotic, adriamycin, for 6 and 10 weeks, respectively. In both groups of treated animals myocardial phosphocreatine content was lower than in control hearts, while ATP content was unchanged. Hearts of treated animals exhibited only a minor depression of cardiac output with a submaximal pressure load or during volume overload. However, at maximal pressure load GPA- and adriamycin-treated hearts performed 43% and 37% less pressure-volume work than control hearts. These changes were due both to decreased LV pressure development and diminished cardiac output. LV diastolic stiffness was significantly higher at the submaximal pressure load and the LV filling pressure area, which reflected LV filling, was lower in hearts of both treated groups. The differences in both indices were exaggerated when the maximal pressure load was applied. Limited LV filling due to incomplete myocardial relaxation appeared to represent the underlying cause of cardiac failure when afterload was increased. These results may be explained if adaptation of cardiac contractile function in some chronic cardiac diseases arises from a limited energy supply to the myofibrils.
J Mol Cell Cardiol 1989 Feb
PMID:Adaptation of cardiac contractile function to conditions of chronic energy deficiency. 273 32

The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
Mol Cell Biochem
PMID:Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. 277 37


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