Nitric oxide inhibits cardiac energy production via inhibition of mitochondrial creatine kinase.
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Nitric oxide biosynthesis in cardiac muscle leads to a decreased oxygen consumption and lower ATP synthesis. It is suggested that this effect of nitric oxide is mainly due to the inhibition of the mitochondrial respiratory chain enzyme, cytochrome c oxidase. However, this work demonstrates that nitric oxide is able to inhibit soluble mitochondrial creatine kinase (CK), mitochondrial CK bound in purified mitochondria, CK in situ in skinned fibres as well as the functional activity of mitochondrial CK in situ in skinned fibres. Since mitochondrial isoenzyme is functionally coupled to oxidative phosphorylation, its inhibition also leads to decreased sensitivity of mitochondrial respiration to ADP and thus decreases ATP synthesis and oxygen consumption under physiological ADP concentrations. (+info)
Separation of urea, uric acid, creatine, and creatinine by micellar electrokinetic capillary chromatography with sodium cholate.
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The capillary electrophoretic separation of the four nonprotein nitrogenous compounds (NPNs; urea, uric acid, creatine, and creatinine) typically employed in clinical and medical settings for the monitoring of renal function is described. Successful resolution of these compounds is achieved with the use of a bile salt micelle system composed of sodium cholate at phosphate buffer pH 7.4. The elution patterns of four NPNs are obtained within 30 min with a voltage of 30 kV. The effect of varying the applied voltage, temperature, and the mole ratio of phosphate buffer with bile salt surfactant on the migration behavior is also examined. (+info)
Shortening of muscle relaxation time after creatine loading.
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The effect of creatine (Cr) supplementation on muscle isometric torque generation and relaxation was investigated in healthy male volunteers. Maximal torque (Tmax), contraction time (CT) from 0.25 to 0.75 of Tmax, and relaxation time (RT) from 0.75 to 0.25 of Tmax were measured during 12 maximal isometric 3-s elbow flexions interspersed by 10-s rest intervals. Between the pretest and the posttest, subjects ingested Cr monohydrate (4 x 5 g/day; n = 8) or placebo (n = 8) for 5 days. Pretest Tmax, CT, and RT were similar in Cr and placebo groups. Also in the posttest, Tmax and CT were similar between groups. However, posttest RT was decreased consistently by approximately 20% (P < 0.05) in the Cr group from the first to the last of the 12 contractions. In addition, the mean decrease in RT after Cr loading was positively correlated with pretest RT (r = 0.82). It is concluded that Cr loading facilitates the rate of muscle relaxation during brief isometric muscle contractions without affecting torque production. (+info)
Absolute quantification of brain metabolites by proton magnetic resonance spectroscopy in normal-appearing white matter of multiple sclerosis patients.
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The aim of this research was to obtain an absolute quantification of the N-acetyl-aspartate, choline, creatine and phosphocreatine levels in normal-appearing white matter by means of 1H magnetic resonance spectroscopy in a group of multiple sclerosis patients (27 with the relapsing-remitting form and 13 with the secondary progressive form). These values were compared with those of a group of 12 age-matched healthy control subjects. A significant decrease in the N-acetyl-aspartate concentration was found in normal-appearing white matter of frontal and parietal brain areas in multiple sclerosis patients compared with the same areas in control subjects. This reduction was more evident in progressive patients. The decrease in the N-acetyl-aspartate concentration in normal-appearing white matter significantly correlated with the Expanded Disability Status and the lesional load. No significant change was found in the concentration of creatine or choline. This finding concurs with previous evidence of heterogeneity in the multiple sclerosis pathological process which is not confined to the lesions and involves not only myelin, but also axons, even in white matter which appears normal on MRI. (+info)
Efficiency of oxidative phosphorylation and energy dissipation by H+ ion recycling in rat-liver mitochondrial metabolizing pyruvate.
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A method was developed for the calculation of metabolic fluxes through individual enzymatic reactions of pyruvate metabolism including the citric acid cycle in rat liver mitochondrial incubated at metabolic states between state 4 and state 3. This method is based on the measurement of the specific radioactivities of the products formed from [2-14C]pyruvate. With this procedure the energy balance of mitochondria incubated in the presence of [2-14C]pyruvate, ATP, bicarbonate and phosphate at different ATP/ADP ratios in the medium was calculated. The ATP/ADP ratios were maintained at a steady state with creatine kinase plus creatine as a phosphoryl acceptor. The calculations revealed that by adding increasing concentrations of creatine up to 20 mM the energy dissipated by the mitochondria decreased but showed a local maximum at 13mM creatine. Omission of bicarbonate from the medium led to a shift of this maximum. When energy dissipation was minimal the overall P/O ratio was maximal. The amount of energy dissipated was paralleled by the magnitude of the pH gradient across the inner membrane. From these results it was concluded that the recycling of H+ ions which consists of a passive leakage of H+ ions into the matrix and an active extrusion of these ions out of this compartment, is an important energy dissipating process. The H+ ion recycling is thus one of the processes which give rise to the state 4 respiration in mitochondria. (+info)
Cerebral metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy.
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OBJECTIVES: Using proton magnetic resonance spectroscopy, we investigated cerebral metabolism and its determinants in congestive heart failure (CHF), and the effects of cardiac transplantation on these measurements. BACKGROUND: Few data are available about cerebral metabolism in CHF. METHODS: Fifty patients with CHF (ejection fraction < or = 35%) and 20 healthy volunteers were included for this study. Of the patients, 10 patients underwent heart transplantation. All subjects performed symptom-limited bicycle exercise test. Proton magnetic resonance spectroscopy (1H MRS) was obtained from localized regions (8 to 10 ml) of occipital gray matter (OGM) and parietal white matter (PWM). Absolute levels of the metabolites (N-acetylaspartate, creatine, choline, myo-inositol) were calculated. RESULTS: In PWM only creatine level was significantly lower in CHF than in control subjects, but in OGM all four metabolite levels were decreased in CHF. The creatine level was independently correlated with half-recovery time and duration of heart failure symptoms in PWM (r = -0.56, p < 0.05), and with peak oxygen consumption and serum sodium concentration in OGM (r = 0.58, p < 0.05). Cerebral metabolic abnormalities were improved after successful cardiac transplantation. CONCLUSIONS: This study shows that cerebral metabolism is abnormally deranged in advanced CHF and it may serve as a potential marker of the disease severity. (+info)
Effect of thrombin inhibition in vascular dementia and silent cerebrovascular disease. An MR spectroscopy study.
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BACKGROUND AND PURPOSE: Silent cerebrovascular disease (CVD) has been proposed as a predisposing condition for clinically overt stroke and vascular dementia. Recently, we found increased thrombin generation in silent CVD patients. Here, we report the effect of thrombin inhibition using a potent selective thrombin inhibitor on the cerebral metabolism and function in peripheral arterial occlusive disease (PAOD) patients with or without silent CVD. METHODS: We examined 17 mild chronic PAOD patients, including 2 cases of vascular dementia. We divided the patients into 2 groups: 1 was the advanced CVD group with multiple lacunar infarction and/or advanced periventricular hyperintensity detected by brain MRI (n=12), and the other was the no CVD group that had none of these abnormalities (n=5). We assessed the cerebral biochemical compounds in the deep white matter area and cerebellar hemisphere (8 cm3) by proton MR spectroscopy before and after infusion of argatroban (10 mg/d IV) over 2 hours for 7 days. RESULTS: The ratio of N-acetylasparate (NAA) to total creatine (Cre) in the deep white matter area was significantly lower in the advanced CVD group than in the no CVD group, whereas there were no significant differences in this ratio in the cerebellar hemisphere between the 2 groups. In the former group, this decreased NAA/Cre ratio significantly increased after argatroban therapy, whereas there was no change in the latter group. The 2 patients with vascular dementia showed clinical improvement with marked increases in the NAA/Cre ratio and mini-mental score. CONCLUSIONS: These results suggest that increased thrombin generation may have some pathophysiological roles in developing vascular dementia and its chronic predisposing conditions. Thrombin inhibition may break this vicious cycle and lead to clinical improvement. (+info)
Proton MR spectroscopy in patients with complex partial seizures: single-voxel spectroscopy versus chemical-shift imaging.
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BACKGROUND AND PURPOSE: Proton MR spectroscopy has recently been applied to the evaluation of seizures, but few comparisons have been made between different clinical spectroscopic techniques. Our goal was to determine whether there is a significant difference between hippocampal NAA/(Cho+Cr) ratios obtained by single-voxel spectroscopy (SVS) and by chemical-shift imaging (CSI). METHODS: Twelve healthy adults and eight patients with complex partial seizures were studied on a 1.5-T MR scanner using a proton SVS method. Another 12 healthy adults and 10 patients with complex partial seizures were recruited for a proton CSI study, which was performed on a different 1.5-T MR system. The NAA/(Cho+Cr) ratio was calculated from the integral peak areas by curve fitting. The two-tailed t-test was used for statistical analysis. RESULTS: The mean value +/- standard deviation of the hippocampal NAA/(Cho+Cr) ratio in healthy control subjects was 0.63 +/- 0.07 by SVS, with 0.62 +/- 0.15 for the anterior hippocampus and 0.65 +/- 0.11 for the posterior hippocampus by CSI. There was no significant difference between the control group data obtained by SVS and those by CSI, nor was there a regional difference in the CSI NAA/(Cho+Cr) ratio in the hippocampus. Relative to the control group, the patients with seizures had a significant decrease in the NAA/(Cho+Cr) ratio in the abnormal hippocampus: -28% by SVS, and -24% in the anterior hippocampus and -18% in the posterior hippocampus by CSI. Proton SVS and CSI detected hippocampal abnormalities, unilateral or bilateral, in all patients of each group. CONCLUSION: Under similar measurement conditions, proton SVS and CSI provide similar NAA/(Cho+Cr) ratios among healthy control subjects, and they possess comparable ability for detecting hippocampal abnormalities in patients with complex partial seizures. (+info)