Increase in blood bradykinin concentration after eccentric weight-training exercise in men.
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The purpose of this study was to verify the possible appearance in the blood of bradykinin (BK) and des-Arg(9)-bradykinin (des-Arg(9)-BK) after eccentric exercise in 13 male subjects. Eccentric exercise (5 x 10 leg presses at 120% maximal voluntary concentric contraction) resulted in muscle damage and inflammation, as suggested by the significant increase in serum creatine kinase activity (from 204 +/- 41 to 322 +/- 63 U/l 12 h postexercise) and by severe lasting pain, which also peaked at 12 h postexercise. Blood BK and des-Arg(9)-BK concentrations were measured by competitive enzyme immunoassays using highly specific polyclonal rabbit IgG. Des-Arg(9)-BK concentration was not modified (preexercise: 44 +/- 14 pmol/l; pooled postexercise: 47 +/- 4 pmol/l). In contrast, BK concentration significantly increased immediately after the exercise session (68 +/- 9 vs. 42 +/- 3 pmol/l preexercise) and returned to basal values at 12, 24, and 48 h (pooled value: 40 +/- 4 pmol/l). This observation suggests that the inflammatory process due to eccentric exercise-induced muscle damage could be mediated in part by BK. (+info)
Muscle degeneration without mechanical injury in sarcoglycan deficiency.
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In humans, mutations in the genes encoding components of the dystrophin-glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding alpha-, beta-, gamma-, and delta-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking gamma-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without gamma-sarcoglycan, beta- and delta-sarcoglycan are unstable at the muscle membrane and alpha-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-alpha2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking gamma-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycan-deficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking gamma-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient. (+info)
Epidemiological classification of acute myocardial infarction: time for a change?
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AIMS: The classification of an acute ischaemic cardiac event is traditionally based on cardiac enzymes, electrocardiography (ECG) and clinical symptoms. The impact of new specific cardiac markers on the diagnostic classification of suspected acute myocardial infarction remains poorly studied. We therefore set out to compare the diagnostic and prognostic information provided by the MONICA code and a patient classification based on the maximal level of creatine kinase MB isoenzyme. The significance of typical pain and various ECG algorithms were separately analysed. METHODS AND RESULTS: The study population consisted of 311 consecutive patients who were evaluated for suspected acute myocardial infarction in a regional referral hospital. Patients were retrospectively classified according to the MONICA criteria, by a simplified code combining symptoms and creatine kinase MB, and solely using the maximal creatine kinase MB concentration. Total mortality was followed for 1 and 5 years. The creatine kinase MB based classification was shown to be the strongest predictor of mortality (OR=2.8-3.7, p<0.001) for outcome both at 1 and 5 years. Typical pain and a positive Minnesota ECG had no prognostic relevance. However, an analysis algorithm of the admission ECG was predictive of 1- and 5-year survival. CONCLUSIONS: The epidemiological classification of suspected acute myocardial infarction could be based solely on a specific cardiac marker, such as creatine kinase MB mass. This approach contains prognostic information and is accurate enough for the structured diagnosis of acute myocardial infarction. Other outcome predictors could be used to identify patient subgroups and assess therapy. (+info)
Endogenously produced lipoprotein lipase enhances the binding and cell association of native, mildly oxidized and moderately oxidized low-density lipoprotein in mouse peritoneal macrophages.
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It has been well established that purified lipoprotein lipase (LPL) can facilitate the cellular uptake of various native and modified lipoproteins when added exogenously to macrophages. Because activated macrophages express LPL endogenously, it was the aim of this study to investigate the effect of macrophage-produced LPL on the uptake of native low-density lipoprotein (LDL) and LDL that has been modified to various degrees by Cu(2+)-mediated oxidation. Cell binding and uptake of Eu(3+)-labelled native and oxidized LDL was determined in mouse peritoneal macrophages (MPM) from normal mice and induced mutant mice that lack LPL expression in MPM. We found that LPL expressed by MPM was able to increase cell binding and association of native LDL (by 121% and 101% respectively), mildly oxidized LDL (by 47% and 43%) and moderately oxidized LDL (by 30% and 22%). With increased levels of lipoprotein oxidation, the relative proportion of LPL-mediated LDL uptake decreased. This decrease was not due to weakened binding of LPL to oxidized LDL. The drastically increased uptake of highly oxidized LDL in MPM by scavenger-receptor-mediated pathways might dominate the simultaneous exogenous or endogenous LPL-mediated uptake of this lipoprotein. Competition experiments with positively charged poly(amino acids) furthermore suggested that histidine, arginine and lysine residues in LPL are important for the interaction between LDL and LPL. Our results imply that physiological levels of LPL produced by macrophages facilitate the uptake of native LDL as well as mildly and moderately oxidized LDL. This process might, in the micro-environment of arteries, contribute to the accumulation of macrophage lipids and the formation of foam cells. (+info)
Kinetics of cyclocreatine and Na(+) cotransport in human breast cancer cells: mechanism of activity.
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The growth-inhibitory effect of cyclocreatine (CCr) and the kinetics of CCr and Na(+) cotransport were investigated in MCF7 human breast cancer cells and its adriamycin-resistant subline with use of (31)P- and (23)Na-NMR spectroscopy. The growth-inhibitory effect in the resistant line occurred at a lower CCr concentration and was more pronounced than in the wild-type line. This correlated with an approximately 10-fold higher affinity of CCr to the transporter in the resistant line. The passive diffusion coefficient of CCr was also higher in the resistant line by three- to fourfold. The transport of CCr was accompanied by a rapid increase in intracellular Na(+). This increase was found to depend on the rate of CCr transport and varied differently with CCr concentration in the two cell lines. It is proposed that the cotransport of CCr and Na(+) followed by increased Na(+) concentration, together with the accumulation of the highly charged phosphocyclocreatine, are responsible for cell swelling and death. (+info)
Loss of GSH and thiol enzymes in endothelial cells exposed to sublethal concentrations of hypochlorous acid.
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We investigated the effect of sublethal concentrations of hypochlorous acid (HOCl) on intracellular thiol groups. Exposure of human umbilical vein endothelial cells to HOCl caused a decrease in cell viability, with concentrations of +info)
Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial.
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BACKGROUND: Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non-Q-wave myocardial infarction (UA/NQMI). METHODS AND RESULTS: Patients (n=3910) with UA/NQMI were randomized to intravenous UFH for >/=3 days followed by subcutaneous placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute phase (initial 30 mg intravenous bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for those weighing >/=65 kg). The primary end point (death, myocardial infarction, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (OR 0.83; 95% CI 0.69 to 1.00; P=0. 048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00; P=0.048). During the first 72 hours and also throughout the entire initial hospitalization, there was no difference in the rate of major hemorrhage in the treatment groups. During the outpatient phase, major hemorrhage occurred in 1.5% of the group treated with placebo and 2.9% of the group treated with enoxaparin (P=0.021). CONCLUSIONS: Enoxaparin is superior to UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of UA/NQMI patients without causing a significant increase in the rate of major hemorrhage. No further relative decrease in events occurred with outpatient enoxaparin treatment, but there was an increase in the rate of major hemorrhage. (+info)
Endurance exercise causes interaction among stress hormones, cytokines, neutrophil dynamics, and muscle damage.
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We analyzed adaptation mechanisms regulating systemic inflammatory response of the stressed body by using an experimental challenge of repeated exercise bouts and accompanying muscle inflammation. Eight untrained men bicycled at 90 W for 90 min, 3 days in a row. Exercise induced peripheral neutrophilia with a leftward shift of neutrophil nucleus and neutrophil priming for oxidative activity determined by luminol-dependent chemiluminescence. Plasma growth hormone and interleukin-6 rose significantly after exercise and were closely correlated with the neutrophil responses. Serum creatine kinase and myoglobin levels as muscle damage markers rose after exercise in "delayed onset" and were closely correlated with the preceding neutrophil responses. These exercise-induced responses were strongest on day 1, but the magnitude gradually decreased with progressive daily exercise. In contrast, the magnitude of catecholamine responses to exercise sessions gradually rose, possibly suppressing neutrophil oxidative responses. These results indicate that stress-induced systemic release of bioactive substances may determine neutrophil mobilization and functional status, which then may affect local tissue damage of susceptible organs. (+info)