scholarly journals The mechanisms of cardiac protection using a synthetic agonist of galanin receptors during chronic administration of doxorubicin

Acta Naturae ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 89-98
Author(s):  
Irina M. Studneva ◽  
Oksana М. Veselova ◽  
Arthur A. Bahtin ◽  
Galina G. Konovalova ◽  
Vadim Z. Lankin ◽  
...  
Keyword(s):  
Adenine Nucleotide ◽  
Chronic Administration ◽  
Protective Mechanism ◽  
Creatine Kinase Mb ◽  
Total Creatine ◽  
Adenine Nucleotide Pool ◽  
Galanin Receptors ◽  
Increased Activity ◽  
Peptide G ◽  
Anthracycline Chemotherapy

The use of the anticancer drug doxorubicin (Dox) is limited by its cardiotoxic effect. The aim of this work was to study the effect of a new synthetic agonist of the galanin receptor GalR1-3 [Ala14, His15]-galanine (215) (G) on the metabolism, antioxidant enzyme activity, and cardiac function in rats with cardiomyopathy (CM) caused by chronic administration of Dox. Coadministration of peptide G and Dox significantly increased the fractional shortening (FS) and ejection fraction (EF) by an average of 30 4% compared with the indices in the Dox group. The reduced severity of cardiac dysfunction under the action of G was accompanied by a 2.5-fold decrease in the activity of creatine kinase-MB (CK-MB) in blood plasma. The protective mechanism of the action of peptide G is caused by a reduced lipid peroxidation (LP) that is due to the increased activity of Cu,Zn superoxide dismutase (Cu,Zn-SOD) and glutathione peroxidase (GSH-Px) in the damaged heart. Administration of peptide G significantly increased the adenine nucleotide pool (AH), ATP content, and the levels of phosphocreatine (PCr) and total creatine (Cr) in the damaged myocardium. It also reduced lactate accumulation relative to its content in the Dox group. The better energy supply of cardiomyocytes after treatment with peptide G prevented the accumulation of cytotoxic ammonia and disruption in the metabolism of the key myocardial amino acids (glutamic acid (Glu), aspartic acid (Asp), and alanine (Ala)). Peptide G significantly improved the morphological parameters of the heart in rats treated with Dox. The results show promise in using peptide G to efficiently correct functional, morphological, and metabolic damage to the heart caused by anthracycline chemotherapy.

Analysis of metabolic control: new insights using scaled creatine kinase model

1988 ◽  
Vol 254 (6) ◽  
pp. R949-R959 ◽  
Author(s):  
R. J. Connett
Keyword(s):  
Creatine Kinase ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Binding Constants ◽  
Cation Binding ◽  
Ph Values ◽  
Total Phosphate ◽  
Total Creatine ◽  
The Stability ◽  
Adenine Nucleotide Pool

The creatine kinase-adenylate kinase equilibria equations are given a dimensionless form by normalizing to total creatine concentration. Analysis with appropriate equilibrium and cation-binding constants identified two sharply separated phases of energy depletion. In the "buffering" phase, energy is derived from phosphocreatine. In the "depleting" phase, adenine nucleotides are the source of energy. Defining the state of the adenine nucleotide pool requires only pH, phosphocreatine, and creatine concentrations. Analysis of data from skeletal muscle, heart, brain, and smooth muscle demonstrated that the [free adenine nucleotide]/[total creatine] and [total phosphate]/[total creatine] are essentially constant over the greater than 20-fold concentration range among tissues and species. This result permits quantitative evaluation of cell energetics with data scaled to the total phosphate, as obtained with nuclear magnetic resonance studies, or to total creatine, as obtained in chemical analysis of freeze-trapped tissue. By applying the stability of the tissue parameters to the equations, it is demonstrated that unique identification of a hypothesis describing the recruitment of O2 uptake requires testing at several pH values.

Secretion of creatine kinase MB isoenzyme by an immature teratoma with predominant rhabdomyosarcomatous elements.

1988 ◽  
Vol 34 (12) ◽  
pp. 2600-2602 ◽  
Author(s):  
K Emancipator ◽  
A P Kudelka ◽  
G Bradford ◽  
K A Leonard ◽  
M H Zarrabi
Keyword(s):  
Creatine Kinase ◽  
Coronary Atherosclerosis ◽  
Kinase Activity ◽  
Creatine Kinase Activity ◽  
Immature Teratoma ◽  
Malignant Teratoma ◽  
Creatine Kinase Mb ◽  
Total Creatine Kinase Activity ◽  
Total Creatine ◽  
Increased Activity

Abstract A 37-year-old man with metastatic immature (malignant) teratoma with prominent rhabdomyosarcomatous elements had markedly increased activity of creatine kinase (EC 2.7.3.2) MB in serum. There was no electrocardiographic evidence of infarction or ischemia, and autopsy revealed no myocardial infarction, significant coronary atherosclerosis, myocarditis, or invasion of the heart by tumor. A high proportion of the creatine kinase activity in a homogenate of the tumor was attributable to the MB isoenzyme. Persistent increases of creatine kinase-MB and an unusually high MB isoenzyme activity, out of proportion to total creatine kinase activity, may indicate a nonmyocardial origin of this isoenzyme.

scholarly journals Protective action of a modified fragment of galanine in rats with doxorubicin-induced heart failure

2019 ◽  
Vol 65 (1) ◽  
pp. 51-56 ◽  
Author(s):  
I.M. Studneva ◽  
M.E. Palkeeva ◽  
O.M. Veselova ◽  
A.S. Molokoedov ◽  
R.O. Lubimov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Weight Gain ◽  
Cardiac Function ◽  
High Energy ◽  
High Energy Phosphates ◽  
Creatine Kinase Mb ◽  
Galanin Receptors ◽  
Group D ◽  
Peptide G ◽  
Plasma Tbars

The use of the anticancer drug doxorubicin (Dox) is limited due to its cardiotoxic effect. Using the method of automatic solid-phase peptide synthesis, we obtained a synthetic agonist of galanin receptors GalR1-3 [RAla14, His15]-galanine (2-15) (G), exhibiting cardioprotective properties. It was purified by high performance liquid chromatography (HPLC). The homogeneity and structure of the peptide was confirmed by HPLC, 1H-NMR spectroscopy and mass spectroscopy. The purpose of this study was to study the effect of G on the metabolism and cardiac function of rats with chronic heart failure (CHF) caused by Dox. Experiments were performed using male Wistar rats weighing 280-300 g. The control group of animals (C) was intraperitoneally treated with saline for 8 weeks; the doxorubicin group (D) of rats was intraperitoneally treated with Doх; the group of Doх + peptide G (D+G) received intraperitoneally injections of Doх and subcutaneously injections of peptide G; the peptide G group (G) was subcutaneously treated with G. At the beginning and at the end of the study, the concentration of thiobarbituric acid reactive substances (TBARS) and the activity of creatine kinase-MB (CK-MB) were determined in blood plasma; the animals were weighed, and cardiac function was assessed using echocardiography. At the end of the experiments, the hearts were used for determination of metabolites and assessment of oxidative phosphorylation in mitochondria. After 8-week treatment, animals of group D were characterized by severe heart failure, the lack of weight gain and an increase in plasma TBARS concentration and CK-MB activity. These disorders were accompanied by a decrease in the content of myocardial high-energy phosphates, a reduction inmitochondrial respiratory parameters, accumulation of lactate and glucose in the heart, and disturbances in the metabolism of alanine and glutamic and aspartic acids. Coadministration of G and Dox prevented the increase in plasma CK-MB activity and significantly reduced the plasma TBARS concentration. At the end of the experiments animals of group D+G had higher myocardial energy state and the respiratory control index of mitochondria than animals of group D, there was a decrease in anaerobic glycolysis and no changes in the amino acid content compared to the control. The peptide G significantly improved the parameters of cardiac function and caused weight gain in animals of group D+G in comparison with these parameters in group D. The obtained results demonstrate the ability of a novel agonist of galanin receptors GalR1-3 to attenuate Dox-indiced cardiotoxicity.

Inhibition of xanthine oxidase ameliorates functional and metabolic impairment in type 2 diabetic hearts under pressure overload

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Igaki ◽  
A Osanami ◽  
M Tanno ◽  
T Sato ◽  
T Ogawa ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Adenine Nucleotide ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Diabetic Control ◽  
Funding Source ◽  
National Budget ◽  
Adenine Nucleotide Pool

Abstract Background We recently reported that upregulated AMP deaminase (AMPD), via reduction in the tissue adenine nucleotide pool, contributes to exacerbation of diastolic dysfunction under pressure overload in OLETF, a rat model of obese type 2 diabetes (T2DM). Upregulated AMPD also possibly promotes xanthine oxidase (XO)-mediated ROS production, since AMPD deaminases AMP to IMP, which is further converted to inosine, providing substrates of XO, hypoxanthine and xanthine. Here, we examined the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction by suppression of ROS-mediated mitochondrial dysfunction and/or vascular dysfunction in T2DM rats. Methods and results Metabolomic analyses revealed that levels of xanthine and uric acid in the LV myocardium were significantly higher by 37% and 51%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of phenylephrine-induced pressure overloading (200–230 mmHg). Myocardial XO activity in OLETF was 57.9% higher than that in LETO, which may be attributed to 31% higher level of inosine, a positive regulator of XO, in OLETF than in LETO. The activity of XO was significantly attenuated by administration of topiroxostat, an XO inhibitor at 0.5 mg/kg/day for 14 days. Pressure volume loop analyses showed that the pressure overloading resulted in significantly higher LVEDP in OLETF than in LETO (18.3±1.5 vs. 12.2±1.3 mmHg, p<0.05, n=7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6±0.4 vs. 4.7±0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3±1.5 vs. 11.3±1.1 mmHg, p<0.05) but not in LETO. Under the condition of pressure overloading, Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3±0.3 vs. 1.6±0.3, p<0.05), and it was also improved by topiroxostat in OLETF (1.2±0.2, p<0.05). Myocardial ATP content was lower in OLETF than in LETO (2966±400 vs. 1818±171 nmol/g wet tissue, p<0.05), and treatment with topiroxostat significantly restored the ATP level (2629±307 nmol/g wet tissue). The LV myocardium of OLETF under pressure overload showed significantly higher level of malondialdehyde and 4-hydroxynonenal, an indicator of lipid peroxidation, than that of LETO. Measurement of oxygen consumption rate by Seahorse XFe96 Analyzer in mitochondria isolated from LV tissues revealed that state 3 respiration was significantly suppressed in OLETF by 43% compared to LETO, and it was restored by treatment with topiroxostat. Conclusion Both activity and substrates of XO are increased in T2DM hearts, in which upregulation of AMPD may play a role. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling in diabetic hearts, most likely through protection of mitochondrial function from ROS-mediated injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for Scientific Research (#26461132, #17K09584) from the Japanese Society for the Promotion of Science

scholarly journals The role of glutamine oxidation and the purine nucleotide cycle for adaptation of tumour energetics to the transition from the anaerobic to the aerobic state

1988 ◽  
Vol 252 (2) ◽  
pp. 381-386 ◽  
Author(s):  
Z Kovacević ◽  
D Jerance ◽  
O Brkljac
Keyword(s):  
Adenine Nucleotide ◽  
The Other ◽  
Purine Nucleotide ◽  
Purine Nucleotide Cycle ◽  
Adenine Nucleotide Pool

It is proposed that the purine nucleotide cycle and glutamine oxidation play a key role in the adaptation of tumour energetics to the transition from the anaerobic to the aerobic state. In support of this proposal, it was found that glutamine and inosine markedly increase total adenylates in the presence of oxygen, whereas the addition of hadacidin abolishes this effect. Transition of the cells from the anaerobic to the aerobic state, and vice versa, in the presence of glutamine plus inosine revealed that there are two components of the adenine nucleotide pool, one which is stable and the other which is variable and responds to the aerobic-anaerobic transition. This part of the pool undergoes degradation or resynthesis owing to activation of the enzymes of the purine nucleotide cycle. Resynthesis of the pool is accompanied by substantial net utilization of aspartate, which is produced by glutamine oxidation. This is supported by the experiments in which the cells were alternately incubated with nitrogen or oxygen, demonstrating that hadacidin significantly decreased utilization of aspartate and regeneration of ATP owing to inhibition of adenylosuccinate synthase.

Early effects of phenobarbital on the adenine nucleotide pool of rat liver

1972 ◽  
Vol 21 (14) ◽  
pp. 1929-1934 ◽  
Author(s):  
Roy McCauley ◽  
John O'Neill ◽  
Daniel Couri
Keyword(s):  
Rat Liver ◽  
Adenine Nucleotide ◽  
Early Effects ◽  
Adenine Nucleotide Pool

scholarly journals Nucleotide and Serotonin Metabolism in Platelets With Defective Secondary Aggregation

Blood ◽  
1974 ◽  
Vol 44 (6) ◽  
pp. 789-800 ◽  
Author(s):  
F. I. Pareti ◽  
H. J. Day ◽  
D. C. B. Mills
Keyword(s):  
Platelet Aggregation ◽  
Adenine Nucleotide ◽  
Platelet Rich Plasma ◽  
Adenine Nucleotides ◽  
Rapid Rate ◽  
Serotonin Metabolism ◽  
Release Reaction ◽  
Atp Breakdown ◽  
Platelet Defects ◽  
Adenine Nucleotide Pool

Abstract Ten patients with qualitative platelet defects have been investigated. All of the patients had impairment of secondary platelet aggregation induced by ADP, epinephrine, and collagen, and a defective release reaction. In seven patients from four families, the abnormality was consistent with the lack of a metabolically inert adenine nucleotide pool. Four of these patients, from two families, were albinos. Platelets from all of these patients had lower than normal amounts of adenine nucleotides and 5HT; the ability of these platelets to incorporate the amine was reduced and 5HT was metabolized at an abnormally rapid rate in platelet-rich plasma. It was not possible to distinguish the defect present in the albinos from that in the normally pigmented patients. Three other patients had normal amounts of platelet adenine nucleotides and 5HT; platelet aggregation and the release of adenine nucleotides induced by collagen were impaired. Metabolic ATP breakdown, during collagen aggregation, was also decreased. This defect is similar to that induced in normal platelets by aspirin. Studies on intracellular synthesis of cyclic 3'5' AMP in both groups of patients showed that the platelets were normally responsive to PGE1 and the antagonism of PGE1 by ADP and by epinephrine was also normal.

Purine metabolic pathways in rat hindlimb perfusion model during ischemia and reperfusion

1993 ◽  
Vol 265 (4) ◽  
pp. H1074-H1081 ◽  
Author(s):  
B. Soussi ◽  
K. Lagerwall ◽  
J. P. Idstrom ◽  
T. Schersten
Keyword(s):  
Skeletal Muscle ◽  
Blood Cell ◽  
Xanthine Oxidase ◽  
Flow Rate ◽  
Adenine Nucleotide ◽  
Vascular Endothelial Cell ◽  
Nucleotide Metabolism ◽  
Computer Simulation Model ◽  
Tissue Homogenates ◽  
Adenine Nucleotide Pool

The perfused rat hindlimb preparation was used with a blood cell-free perfusate to investigate alterations in the purine nucleotide metabolism, flow rate, perfusion pressure, and venous excretion in response to ischemia and ischemia followed by reperfusion in skeletal muscle. The development of a physical hindrance during postischemic reperfusion, indicated by an increase in reperfusion pressure and a decrease in flow rate, coincided with a 90% decrease in phosphocreatine and a 50-70% reduction in total adenine nucleotide pool. The reflow impairment could not be explained by blood cell plugging of the capillaries. Washout of several metabolites was demonstrated during reperfusion. Hypoxanthine accumulated intracellularly during ischemia, and a substantial amount of uric acid was excreted into the venous effluent during reperfusion. The experimental data were fitted into a computer simulation model of the purine pathways. The model indicated that AMP deaminase was the predominant enzymatic pathway for the AMP degradation. It was demonstrated that ATP preferably accumulated as inosine-5'-monophosphate during ischemia and that xanthine oxidase was undetectable in skeletal muscle tissue homogenates. However, vascular endothelial cell xanthine oxidase activity responsible for a free radical-induced reperfusion injury could not be excluded.

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