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PubMed1984

Phosphorothioate analogues of adenosine triphosphate as substrates of the mevalonate kinase reaction.

Adenosine 5'-O-(3-thiotriphosphate) (ATP[gamma S]) and the diastereomers of adenosine 5'-O-(1-thiotriphosphate) (ATP[alpha S]) and adenosine 5'-O-(2-thiotriphosphate) (ATP[beta S]) could act as substrates for mevalonate kinase (ATP: mevalonate 5-phosphotransferase, EC 2.7.1.36) in the presence of different activating divalent metal cations. In the presence of Mg2+ the Rp diastereomers of both ATP[alpha S] and ATP[beta S] were the preferred substrates, whereas in the presence of Cd2+ the Sp diastereomers were the more active. Calculation of Vmax/Km values confirmed reversal of the Rp/Sp ratios for ATP[beta S] with Mg2+ [16] and Cd2+ [2], providing evidence that the metal is coordinated to the beta-phosphate at the active site. However, the corresponding ratios were very similar for ATP[alpha S], 0.4 and 0.2 for Mg2+ and Cd2+, respectively, so that it is unlikely that the metal ion was coordinated to the alpha-phosphate, in the active complex. The Vmax for CdATP [gamma S] was some 90-fold less than that for MgATP[gamma S], suggesting that Cd2+ is bound to S from the gamma-P and that the breaking of the Cd-S bond is the rate determining step of the reaction. It was concluded that the chelate structure of metal ATP substrate in the mevalonate kinase reaction is the lambda,beta,gamma-bidentate MgATP chelate. The probable product of the reaction is delta,alpha,beta-bidentate MgADP.

Adenosine Triphosphate↗
PubMed1988

On the mechanisms of cardiac electrophysiologic actions of adenosine and adenosine 5'-triphosphate.

Adenosine and ATP exert pronounced electrophysiologic actions on the mammalian heart including a negative chronotropic action on cardiac pacemakers and a negative dromotropic action on atrioventricular conduction. These actions are modulated by complex interactions of the two compounds with the autonomic nervous system. Since both adenosine and ATP are released from myocardial cells under physiologic and pathophysiologic conditions, they could play an important modulating role in cardiac electrophysiology. Indeed, studies during the last decade have yielded strong evidence for the role of adenosine in the genesis of specific arrhythmias associated with myocardial ischemia. Further studies are required to fully elucidate the mechanisms of actions of adenosine and ATP in vivo. These will undoubtedly enhance the understanding of the potential arrhythmogenic, as well as the antiarrhythmic actions of endogenous and exogenous adenosine and ATP.

Adenosine↗
PubMed1999

Effect of arrest time and cerebral perfusion pressure during cardiopulmonary resuscitation on cerebral blood flow, metabolism, adenosine triphosphate recovery, and pH in dogs.

OBJECTIVES: To test the hypothesis that greater cerebral perfusion pressure (CPP) is required to restore cerebral blood flow (CBF), oxygen metabolism, adenosine triphosphate (ATP), and intracellular pH (pHi) levels after variable periods of no-flow than to maintain them when cardiopulmonary resuscitation (CPR) is started immediately. DESIGN: Prospective, randomized, comparison of three arrest times and two perfusion pressures during CPR in 24 anesthetized dogs. SETTING: University cerebral resuscitation laboratory. INTERVENTIONS: We used radiolabeled microspheres to determine CBF and magnetic resonance spectroscopy to derive ATP and pHi levels before and during CPR. Ventricular fibrillation was induced, epinephrine administered, and thoracic vest CPR adjusted to provide a CPP of 25 or 35 mm Hg after arrest times of O, 6, or 12 mins. MEASUREMENTS AND MAIN RESULTS: When CPR was started immediately after arrest with a CPP of 25 mm Hg, CBF and ATP were 57 +/- 10% and 64 +/- 14% of prearrest (at 10 mins of CPR). In contrast, CBF and ATP were minimally restored with a CPP at 25 mm Hg after a 6-min arrest time (23 +/- 5%, 16 +/- 5%, respectively). With a CPP of 35 mm Hg, extending the no-flow arrest time from 6 to 12 mins reduced reflow from 71 +/- 11% to 37 +/- 7% of pre-arrest and reduced ATP recovery from 60 +/- 11% to 2 +/- 1% of pre-arrest. After 6- or 12-min arrest times, brainstem blood flow was restored more than supratentorial blood flow, but cerebral pHi was never restored. CONCLUSIONS: A CPP of 25 mm Hg maintains supratentorial blood flow and ATP at 60% to 70% when CPR starts immediately on arrest, but not after a 6-min delay. A higher CPP of 35 mm Hg is required to restore CBF and ATP when CPR is delayed for 6 mins. After a 12-min delay, even the CPP of 35 mm Hg is unable to restore CBF and ATP. Therefore, increasing the arrest time at these perfusion pressures increases the resistance to reflow sufficient to impair restoration of cerebral ATP.

Acid-Base Equilibrium↗
PubMed1987

Voltage-dependent magnesium block of adenosine-triphosphate-sensitive potassium channel in guinea-pig ventricular cells.

1. The adenosine-5'-triphosphate (ATP)-sensitive K+ channel of guinea-pig ventricular cells was examined in the presence and absence of internal Mg2+ or Na+ using an open cell-attached configuration of the patch-clamp technique. 2. Millimolar concentrations of internal Mg2+ ([Mg2+]i) produced marked fluctuations in the outward current, and the amplitude of the open-channel current was reduced with increasing [Mg2+]i. Millimolar Na+ applied internally also decreased the mean amplitude of the outward current, but the increase in current noise was not obvious. These effects became larger when the membrane potential was shifted to be more positive from the K+ equilibrium potential (EK). At potentials negative to EK the inward current was affected by neither internal Mg2+ nor Na+. 3. The external application of Na+, Mg2+ or Ca2+, however, failed to affect the single-channel current. 4. After removal of both internal Mg2+ and Na+, the mean open-channel current-voltage relationship became virtually linear. Referring to these unblocked values, relative amplitudes were determined at different levels of [Mg2+]i or [Na+]i. The dose-response relations gave a Hill coefficient of approximately 1 for Mg2+ block and approximately 2 for Na+ block. The half-maximum concentrations (Kh) for both Mg2+ and Na+ block were shifted to lower values with increasing positive potentials. 5. The power-density spectrum of the open-channel current noise induced by internal Mg2+ showed a Lorentzian function with a corner frequency above 1 kHz, suggesting that the current noise is due to rapid fluctuations of open-channel current between blocked and unblocked states. The corner frequencies gave Mg2+ block and unblock rate constants which were of the order of 10(7) M-1 s-1 and 10(4) s-1, respectively. 6. With increasing external K+ concentration ([K+]o) from 0 to 140 mM the current fluctuations became less prominent, and Kh for Mg2+ block was shifted to higher values. Raising [K+]o enhanced the unblock rate derived from the noise analysis while the block rate was not significantly altered. 7. The above findings could be explained by assuming a binding site for one Mg2+ or two Na+ located 30-35% of the electrical drop across the membrane from the inner mouth of the channel, thereby resulting in the ionic block of K+ passage. An apparent inward rectification observed in the single-channel current-voltage relation is attributable to the blockade of the channel by intracellular Mg2+ and/or Na+.

Action Potentials↗
PubMed1999

Origin of 4-hydroxynonenal incubation-induced inhibition of dopamine transporter and Na+/K+ adenosine triphosphate in rat striatal synaptosomes.

Previous experiments reported that an incubation of striatal synaptosomes with 4-hydroxynonenal (4-HNE) resulted in an inhibition of dopamine (DA) uptake and Na+/K+ adenosine triphosphate (ATPase) activity. The present work investigated whether theses inhibitions are related to a 4-HNE binding to the DA transporter (DAT) and the Na+/K+ ATPase. The number of specific [125I]-PE21 binding sites on the DAT was significantly reduced after incubation with 4-HNE. The Na+/K+ ATPase activity decrease induced by 4-HNE was partially reversed, in a dose-dependent manner, by veratridine, a pump stimulator agent. Our previous data (Morel, P., Tallineau, C., Pontcharraud, R., Piriou, A. and Huguet, F., Effects of 4-hydroxynonenal, a lipid peroxidation product, on dopamine transport and Na+/K+ ATPase in rat striatal synaptosomes. Neurochem. Int., 33 (1999) 531-540) combining with the data observed in this study suggest that changes in DA uptake in striatal synaptosomes are directly related to 4-HNE binding to the DAT, whereas the decrease in Na+/K+ ATPase activity resulted only partially from 4-HNE binding to the pump and is mainly secondary to membrane lipid disruption.

Adenosine Triphosphatases↗
PubMed1998

Sympathetic nervous response relative to the adenosine triphosphate supply-demand imbalance during exercise is augmented in patients with heart failure.

OBJECTIVE: Increase in plasma hypoxanthine (HX) (purine nucleotide degradation product from working muscle) reflects insufficiency of adenosine triphosphate (ATP) supply during exercise, and the exercise-induced increase in plasma norepinephrine (NE) can be an index of sympathetic nerve activity. The aim of this study was to investigate the relationship between plasma NE and plasma HX during exercise in patients with heart failure (HF) according to its severity. METHODS: Blood lactate, plasma HX, and plasma NE were measured at rest and after symptom-limited cardiopulmonary exercise test in 54 patients with HF (New York Heart Association [NYHA] classes I:18, II:20, III:16) and 19 normal subjects. RESULTS: Peak work rate and peak oxygen uptake decreased as the NYHA functional class increased. Blood lactate and plasma HX levels at rest were comparable, but peak blood lactate (normal, NYHA I, II, III: 6.4+/-0.3, 5.6+/-0.4, 5.3+/-0.3, 3.5+/-0.2 mmol/L) and peak plasma HX (3.6+/-0.4, 3.0+/-0.5, 2.4+/-0.3, 1.4+/-0.1 micromol/L) were progressively smaller as HF worsened. Resting plasma NE (137+/-15, 180+/-29, 201+/-21, 318+/-55 pg/mL) was significantly higher in NYHA class III HF, but peak plasma NE (2,235+/-356, 2,021+/-326, 2,188+/-292, 2,210+/-316 pg/mL) was not different among groups. The ratio of the exercise increments in plasma NE to the increments in plasma HX during exercise (deltaplasma NE/deltaplasma HX: 666+/-96, 1,083+/-229, 1,252+/-222, 2,260+/-351) increased according to the severity of HF. CONCLUSION: These data suggest that plasma levels of HX after maximal exercise are smaller as HF worsened, and sympathetic responsiveness to the imbalance of ATP supply-demand during exercise is augmented according to the severity of HF.

Adenosine Diphosphate↗
PubMed2004

The role of adenosine triphosphate citrate lyase in the metabolism of acetyl coenzyme a and function of blood platelets in diabetes mellitus.

Diabetes is known to increase blood platelet activity. Activities of pyruvate dehydrogenase (PDH), adenosine triphosphate (ATP)-citrate lyase (ATPCL), acetyl-coenzyme A (acetyl-CoA) content, malonyl dialdehyde (MDA), synthesis, and platelet aggregation in resting conditions and after activation with thrombin were measured in diabetic subjects and in age- and sex-matched healthy subjects. Activities of ATPCL and PDH, acetyl-CoA content, and thrombin-evoked MDA synthesis as well as platelet aggregation in diabetes were 31%, 51%, 62%, 35%, and 21%, respectively, higher than in healthy subjects. In addition, activation of diabetic platelets caused 2 times greater release of acetyl-CoA from their mitochondria than in controls. Both 1.0 mmol/L (-)hydroxycitrate and 0.1 mmol/L SB-204490 decreased acetyl-CoA content in platelet cytoplasm along with suppression of MDA synthesis and platelet aggregation. These inhibitory effects were about 2 times greater in diabetic than in control platelets. The data presented indicate that the ATPCL pathway is operative in human platelets and may be responsible for provision of about 50% of acetyl units from their mitochondrial to cytoplasmic compartment. Increased acetyl-CoA synthesis in diabetic platelets may be the cause of their excessive activity in the course of the disease. ATPCL may be a target for its specific inhibitors as factors decreasing platelet activity.

ATP Citrate (pro-S)-Lyase↗
PubMed2002

Effects of ZD6169 and ZD0947, 2 potassium adenosine triphosphate channel openers, on bladder function of spinalized rats.

PURPOSE: The use of K+ channel openers is emerging as an attractive possibility for treating bladder overactivity. We tested the efficacy of the 2 adenosine triphosphate dependent K channel openers ZD6169 and ZD0947 on detrusor hyperreflexia after spinal cord injury in rats. MATERIALS AND METHODS: Included in this study were 72 adult Sprague-Dawley rats. Six animals served as normal controls, while 66 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm detrusor hyperreflexia, while another 12 served as control paraplegics. For each drug 24 animals were used and divided into 2 equal groups of 12. Group 1 received the drug in a dose of 3 mg./kg. daily, while group 2 received a dose of 0.3 mg./kg. daily. Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury. RESULTS: Three weeks after spinal cord injury detrusor hyperreflexia developed in all control paraplegic animals with a mean bladder capacity plus or minus standard deviation of 0.7 +/- 0.2 ml. and a mean voiding pressure of 59 +/- 14.2 cm. water. Detrusor hyperreflexia resolved in 66% of the animals that received ZD6169 for 1 week at either dose. For example, mean bladder capacity was 2.5 +/- 1.8 versus 1.8 +/- 1.2 ml. and mean voiding pressure was 42.1 +/- 15.9 versus 43.2 +/- 21.4 cm. water in animals that received 3 versus 0.3 mg./kg. daily, respectively. All animals that received a dose of 3 mg./kg. ZD0947 daily for 1 week showed no detrusor hyperreflexia with a mean bladder capacity of 2.7 +/- 1.8 ml. and mean voiding pressure of 34 +/- 8.5 cm. water, while at 0.3 mg./kg. daily 83% showed no detrusor hyperreflexia with a mean bladder capacity of 2.5 +/- 2.0 ml. and a mean voiding pressure of 41.5 +/- 13.8 cm. water. Each drug produced better urodynamic results when given for 2 weeks. CONCLUSIONS: ZD6169 and ZD0947 are effective treatment for detrusor hyperreflexia after spinal cord injury and they may provide alternative treatment options for overactive bladder. Each drug has time and dose dependent response effects that reflect their wide range of efficacy. However, ZD0947 shows an efficacy profile that is relatively superior to that of ZD6169.

Amides↗
PubMed1995

A novel adenosine triphosphate analog with a heavy atom to target the nucleotide binding site of proteins.

We have synthesized 2'-deoxy-2'-iodoadenosine-5'-triphosphate (2'-IATP), a heavy-atom analog of adenosine-5'-triphosphate. This compound was made for X-ray structural studies to target the nucleotide site of ATP binding proteins. It was diffused successfully into crystals of the microtubule-based motor proteins ncd (non-claret disjunctional protein from Drosophila melanogaster) and kinesin. With ncd, the nucleotide binding site was 70% occupied and the crystals were able to diffract X-rays to 2.5 A. The iodo-analog provided a useful isomorphous derivative with overall phasing power 1.89 in the range of 25.0-2.5 A. With kinesin, 2'-IATP co-crystallized with the protein. The crystals diffracted to at least 2.8 A with a phasing power of 1.73 in the range of 20.0-5.0 A. The analog was also found to be a substrate for all of the enzymes tested, including creatine kinase, pyruvate kinase, hexokinase, and myosin, with values of Km and Vmax that were within a factor of 10 of those for ATP. The analog supported muscle contraction, relaxing fibers, and producing active tension with values not statistically different from those obtained with ATP. These results all suggest that this analog should be useful for providing a heavy-atom derivative for crystals of enzymes that bind ATP.

Adenosine Triphosphatases↗