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Query: UNIPROT:P06889 (Mol)
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The vulnerability of the heart to injury during ischaemia and reperfusion and its responsiveness to various protective and pharmacological interventions are age-dependent. Using three independent indices of tissue injury (cardiac structure, contractile function and creatine kinase leakage), we compared the response of adult (60-90 days old) and neonatal (7 days old) isolated perfused rabbit hearts to global ischaemia and reperfusion. Prior to ischaemia, heart rate was significantly higher in neonatal hearts, as were control values for coronary flow, aortic flow and cardiac output when expressed on a dry wt basis. In experiments in which adult and neonatal hearts (n = 8 per group) were subjected to 2 min of cardioplegia and 45 min of ischaemia, the post-ischaemic recovery of all indices of cardiac function (when expressed as a percentage of pre-ischaemic control) was significantly higher in neonatal than in adult hearts. Thus, cardiac output recovered to 82.9 +/- 3.6% in the neonate but to only 57.9 +/- 6.7% in the adult (P < 0.05). The functional evidence of a greater resistance to ischaemia in the neonate was, however, contradicted by the levels of creatine kinase leakage which tended to be greater in the neonatal than in the adult heart (32.0 +/- 4.7 vs 20.0 +/- 3.1 IU/15 min/g dry wt). Morphological studies indicated that injury was comparable (moderate-to-severe in degree) in both groups. To assess further the relationship between the three indices, additional experiments were undertaken in which the duration of ischaemia in the neonate was extended to 60 min so that the post-ischaemic recovery of function was reduced to a level similar to that seen in the adult after 45 min of ischaemia. Under these conditions cardiac output recovered to 55.6 +/- 4.8% in the neonatal heart (P = NS when compared with the adult) and creatine kinase leakage increased to 88.2 +/- 13.9 IU/15 min/g dry wt--a value over four times greater than that measured in adult hearts with a comparable degree of functional injury. Morphological examination of tissue obtained after 15 min of reperfusion revealed a remarkable recovery of structure in both age groups. In conclusion, in functional terms the neonatal heart was more resistant to ischaemia than the adult; enzymic leakage, however, indicated the opposite and structural assessment revealed no differences. Thus, in comparing injury during ischaemia and reperfusion between different age groups, it is clearly important to employ several independent indices.
J Mol Cell Cardiol 1992 Oct
PMID:Developmental changes in tolerance to ischaemia in the rabbit heart: disparity between interpretations of structural, enzymatic and functional indices of injury. 147 15

The release of cytoplasmic heart fatty acid-binding protein (H-FABP) into the plasma of cardiac patients up to 38 hr after the onset of the first clinical symptoms of acute myocardial infarction (AMI) was studied, using a sensitive direct and noncompetitive Enzyme Linked Immunosorbent Assay of the antigen capture type (sandwich ELISA), newly developed for the measurement of small amounts of human H-FABP in plasma samples. Plasma levels of H-FABP were compared with plasma activity levels of the myocardial cytoplasmic enzymes creatine kinase MB (CK-MB) and alpha-hydroxybutyrate dehydrogenase (alpha-HBDH). Upper normal levels of H-FABP (19 micrograms/l), CK-MB (10 U/l) and alpha-HBDH (160 U/l) as determined in plasma from 72 blood donors served as threshold levels. H-FABP levels were significantly elevated above their threshold level within 3 hr after AMI. Peak levels of H-FABP, CK-MB and alpha-HBDH were reached 4.1 +/- 0.9 hr, 8.4 +/- 1.4 hr and 25.0 +/- 9.5 hr (means +/- S.D., n = 10) after acute myocardial infarction, respectively. Serial time curves of the plasma contents of H-FABP reveal that after myocardial infarction H-FABP is released in substantial amounts from human hearts. In 18 out of 22 patients with established AMI the plasma FABP level was at or above the threshold level in blood-samples taken within 3.5 hr after the first onset of symptoms of AMI, while for CK-MB this applied to 9 patients and for alpha-HBDH to 6 patients. These findings suggest that for an early indication of acute myocardial infarction in man cytoplasmic heart fatty acid-binding protein is more suitable than heart type creatine kinase MB and/or alpha-hydroxybutyrate dehydrogenase.
Mol Cell Biochem 1992 Oct 21
PMID:Release of heart fatty acid-binding protein into plasma after acute myocardial infarction in man. 148 Jan 44

We have examined serum interleukin 6 (IL-6) levels in 12 patients with acute myocardial infarction (AMI). IL-6 levels became elevated in all patients, following the rise of serum creatine kinase (CK) activity. Peak IL-6 levels showed a good correlation with peak serum C-reactive protein (CRP) levels, while there was no direct relationship between peak IL-6 levels and peak CK activity. IL-6 mRNA was not detected in unstimulated "quiescent" rat cardiocytes cultured in serum-free medium, but its expression was induced by exposure of the cells to serum or ionomycin. These results show that IL-6 is synthesized in the myocardium and serum IL-6 levels become elevated in AMI, suggesting that IL-6 could affect the progression and/or healing processes of AMI.
J Mol Cell Cardiol 1992 Jun
PMID:Serum interleukin 6 levels become elevated in acute myocardial infarction. 151 75

The brain type isozyme of creatine kinase (CKB) has proven to be a useful early marker for the action of steroid and other hormones. An increase in the steady state level of mRNA for CKB was found within 30 min after estrogen stimulation of immature rat uteri. Cycloheximide treatment did not inhibit CKB induction. In order to study the molecular mechanism of this induction, 2.9 kb of the 5'-flanking region of CKB fused with the CAT reporter gene was cotransfected into ROS 17/2.8 and HeLa cells along with an expression plasmid for the human estrogen receptor. 17 beta-Estradiol at 10(-8) M or greater concentrations and the antiestrogen tamoxifen at 10(-6) M stimulated CAT activity. When given simultaneously with 17 beta-estradiol, tamoxifen showed a synergistic effect.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Responsiveness of the 5'-flanking region of the brain type isozyme of creatine kinase to estrogens and antiestrogen. 156 43

The present study was undertaken to elucidate a possible role of non-beta-receptor mediated effects in dl-propranolol-induced enhancement of post-hypoxic contractile and metabolic recovery in perfused rat hearts. The rat hearts were perfused for 30 min under reoxygenated conditions following 15 min-substrate free-hypoxic perfusion, and the cardiac performance and myocardial metabolism were examined. Hypoxia induced complete cessation of cardiac contractile force, depletion of myocardial high-energy phosphates, release of ATP metabolites and creatine kinase from the heart. Subsequent reoxygenation produced little recovery of cardiac contractile activity and tissue high-energy phosphates, further enhancement of the release of creatine kinase and the accumulation of tissue calcium. Treatment of the hypoxic hearts with dl-propranolol, d-propranolol and atenolol was performed during 5 to 15 min of hypoxic perfusion. dl-Propranolol and d-propranolol at the concentration of 45 microM elicited a significant recovery of cardiac contractile activity and restoration of myocardial high-energy phosphates. This treatment also resulted in a suppression of the release of creatine kinase and ATP metabolites and the tissue calcium accumulation observed during hypoxia and/or reoxygenation. However, such beneficial effects were not seen in hearts treated with 45 microM atenolol. dl-Propranolol and atenolol, but not d-propranolol, in a concentration of 45 microM have been shown to reveal beta-adrenoceptor blocking action. Thus, the results suggest the involvement of non-beta-receptor mediated effects of propranolol in the enhanced post-hypoxic contractile and metabolic recovery of the perfused rat heart. The non-beta-receptor mediated activity of these drugs appears to be related to their ability to suppress the maximal driving frequency of left atrial preparations.
J Mol Cell Cardiol 1991 Aug
PMID:Enhancement of post-hypoxic contractile and metabolic recovery of perfused rat hearts by dl-propranolol: possible involvement of non-beta-receptor mediated activity. 165 46

The aim of this study was to determine whether acute changes in [Mg2+]free occur during increased hydrolysis of cytosolic ATP, and whether these changes were of sufficient magnitude to be involved in the modulation of myocardial metabolism. 31P-NMR was used to estimate free cytosolic Mg2+ levels ([Mg2+]free) during hypoxia, isoproterenol stimulation, and graded low-flow ischemia in crystalloid perfused, isovolumic rat hearts. Cytosolic [Mg2+]free was calculated to be 0.73 +/- 0.12 mM in control hearts (100 mmHg hydrostatic pressure, 95% O2, n = 18). Cytosolic [Mg2+]free increased gradually during 10 min periods of hypoxia (65%, 50%, 35%, 5% O2), and 20 min infusions of isoproterenol (0.4, 3.0, 75 nM), to maximum values greater than 250% of control (P less than 0.05). During 8 min periods of graded low-flow ischemia (12.0, 7.2, 5.3, 3.4, and 1.6 ml/min/g), [Mg2+]free did not change significantly. [Mg2+]free displayed an inverse linear correlation with total cytosolic [ATP] during isoproterenol infusion (r = 0.87), and an exponential correlation during hypoxia (r = 0.82). The data indicate that acute changes in cytosolic [Mg2+]free can occur during conditions of net ATP hydrolysis although changes in ATP alone do not appear to be solely responsible for the changes in [Mg2+]free. Since the magnitude of the changes in [Mg2+]free are sufficient to alter equilibria of enzymes such as creatine kinase and myokinase, it is possible that these changes are involved in the acute modulation of myocardial metabolism.
J Mol Cell Cardiol 1991 Sep
PMID:Cytosolic free magnesium in stimulated, hypoxic, and underperfused rat heart. 165 49

A myotoxic phospholipase A2, named bothropstoxin II (BthTX-II), was isolated from the venom of the South American snake Bothrops jararacussu and the pathogenesis of myonecrosis induced by this toxin was studied in mice. BthTX-II induced a rapid increase in plasma creatine kinase levels. Histological and ultrastructural observations demonstrate that this toxin affects muscle fibers by first disrupting the integrity of plasma membrane, as "delta lesions" were the earliest morphological alteration and since the plasma membrane was interrupted or absent in many portions. In agreement with this hypothesis, BthTX-II released peroxidase entrapped in negatively charged multilamellar liposomes and behaved as an amphiphilic protein in charge shift electrophoresis, an indication that its mechanism of action might be based on the interaction and disorganization of plasma membrane phospholipids. Membrane damage was followed by a complex series of morphological alterations in intracellular structures, most of which are probably related to an increase in cytosolic calcium levels. Myofilaments became hypercontracted into dense clumps which alternated with cellular spaces devoid of myofibrillar material. Later on, myofilaments changed to a hyaline appearance with a more uniform distribution. Mitochondria were drastically affected, showing high amplitude swelling, vesiculation of cristae, formation of flocculent densities, and membrane disruption. By 24 hr, abundant polymorphonuclear leucocytes and macrophages were observed in the interstitial space as well as inside necrotic fibers. Muscle regeneration proceeded normally, as abundant myotubes and regenerating myofibers were observed 7 days after BthTX-II injection. By 28 days regenerating fibers had a diameter similar to that of adult muscle fibers, although they presented two distinctive features: central location of nuclei and some fiber splitting. This good regenerative response may be explained by the observation that BthTX-II does not affect blood vessels, nerves, or basal laminae.
Exp Mol Pathol 1991 Dec
PMID:Skeletal muscle degeneration and regeneration after injection of bothropstoxin-II, a phospholipase A2 isolated from the venom of the snake Bothrops jararacussu. 166 Aug 22

In this study, we examined the effects of three different beta-blockers, propranolol, pindolol, and metoprolol, on membrane phospholipid preservation in the ischemic and reperfused rat heart. Isolated rat hearts were perfused with Krebs-Henseleit bicarbonate buffer by the Langdendorff technique in the presence or absence of propranolol, pindolol, or metroprolol (20 microM each) for 15 mins at 37 degrees C. Hearts where then either made ischemic alone at 37 degrees C for 30 mins, or followed by 30 mins of reperfusion. Coronary flow and perfusate creatine kinase content were monitored during both pre- and post-ischemic periods. At the end of the experiment, hearts were frozen by freeze-clamping at liquid nitrogen temperature. Membrane phospholipids, fatty acid composition of these phospholipids, non-esterified free fatty acids, and myocardial thiobabituric acid (TBA) reactive product were examined in these hearts. The beta-blocker-treated hearts exhibited significantly less lipid peroxidation than the control hearts (P less than 0.05), as indicated by decreased formation of TBA reactive product and the higher percentage of unsaturated fatty acids in the phosphatidylcholine (PC) in heart. In addition, compared to the control group, less accumulation of free fatty acids was observed in the propranolol and pindolol treated groups. Finally, reduced myocardial creatine kinase release and enhanced recovery of coronary flow indicated significant myocardial preservation by these beta-blockers. The efficacy of these beta-blockers were in the following order: propranolol, pindolol, metoprolol. These results suggest that beta-blockers could also protect an ischemic heart from reperfusion injury by preserving the membrane phospholipids.
J Mol Cell Cardiol 1991 Oct
PMID:Preservation of membrane phospholipids by propranolol, pindolol, and metoprolol: a novel mechanism of action of beta-blockers. 168 6

Postmortem brain tissues of schizophrenic patients were found to contain 5-10 times less water-soluble creatine kinase (BB CK) and 1.5-3 times less mitochondrial creatine kinase as compared to control. The major part of BB CK in schizophrenic brain tissues, contrary to control, was found to be insoluble in water (particulate form of BB CK) and could be extracted from brain tissue with strong denaturating agents. The particulate form of BB CK did not have any enzymatic activity but activity was found after the solubilization of this isoenzyme. The observed BB CK translocation into the particulate inactive form and the decrease of mitochondrial CK content to schizophrenic brains may reflect changes in the synthesis and the utilization of creatine phosphate.
Mol Chem Neuropathol 1991 Dec
PMID:Intracellular alterations of the creatine kinase isoforms in brains of schizophrenic patients. 180 68

The urinary bladder depends on intracellular ATP to support a number of essential intracellular processes including contraction. The concentration of ATP is maintained by mitochondrial oxidative phosphorylation, cytosolic glycolysis and the cytosolic activity of creatine kinase, the enzyme that catalysis the rapid transfer of a phosphate from creatine phosphate (CP) to ADP resulting in the formation of ATP. Prior studies in this lab and others have demonstrated that mitochondrial respiration is significantly lower in hypertrophied bladder tissue (induced by partial outlet obstruction of the white New Zealand Rabbit). In addition to decreased mitochondrial respiration, there are significant increases in glycolysis and lactic acid formation in the hypertrophied tissue. In view of the increased glycolysis and decreased mitochondrial function in the hypertrophied tissue, and the importance in creatine kinase in maintaining cytosolic levels of ATP, the current study was designed to determine if outlet obstruction induces any changes in the activity of creatine kinase. The following is a summary of the results: 1) The bladder mass increased from 2.2 +/- 0.2 gm to 11.5 +/- 1.6 gm at 7 days following outlet obstruction. 2) The intracellular concentrations of both ATP and CP were significantly reduced in the bladder tissue following 7 days of obstruction. 3) The percent of protein (per tissue mass) was significantly lower in the obstructed bladders, although the percent of soluble protein was similar. 4) Creatine kinase activity of control bladders showed linear kinetics with a Vmax = 1120 nmoles/mg protein/4 min and Km = 147 microM CP.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1991 Aug 14
PMID:Creatine kinase activity in normal and hypertrophied rabbit urinary bladder tissue (following partial outlet obstruction). 192 18


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