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Comparison of beat frequencies with rates of dephosphorylation of adenosine triphosphate by glycerinated sea urchin spermatozoa as functions of adenosine triphosphate concentration suggests that each molecule of the flagellar adenosine triphosphatase, dynein, dephosphorylates one adenosine triphosphate molecule during each beat cycle.
Adenosine triphosphate metabolism in caudal epididymis bovine spermatozoa was studied. Measurements by HPLC at appropriate time intervals of the spermatozoa content of ATP and its derivatives were carried out under different experimental conditions. In the presence of 2-D-glucose, cellular ATP was transformed almost quantitatively into ADP and AMP at a rate of 2.3 nmol/min per 10(8) cells. At the same time, ADP and AMP accumulated at a rate of 1.52 and 0.58 nmol/min per 10(8) cells, respectively. In the first 4 min, about 50% of total ATP was degraded, the AEC of the cells dropped to non-physiological values while the content of other nucleosides did not vary significantly. Inorganic P(i) content also remained unchanged. Under non-induced conditions up to 240 min, no variations of the adenylic content and of the EC value was observed. Under induced and non-induced conditions, IMP and adenosine were not detected within the spermatozoa. The lack of IMP might be ascribed either to the absence of AMP deaminase, whose activity has never been found in the spermatozoa or to the intracellular environment which down regulates the activity of the enzyme. In order to explain low levels and absence of variations of adenosine, several enzymic investigations were carried out. Adenosine kinase activity was not determined, therefore the transformation of adenosine into AMP had to be excluded. Nevertheless, enzymic activities potentially able to dephosphorylate the formed AMP are present in the spermatozoa. Our findings are indicative of the existence in the spermatozoa of acid and alkaline phosphatase and of 5'-nucleotidase membrane-derived.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of the adenosine triphosphate analog, 6,6'-dithiobis(inosinyl imidodiphosphate), (sIMP-PNP)2, was tested on the ouabain-sensitive (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 3.6.1.3) and the ouabain-insensitive Mg2+ - ATPase in microsomes prepared from gill tissue of sea water-adapted rainbow trout, Salmo gairdneri. The (Na+ + K+)-ATPase was completely inhibited by low concentrations of (sIMP-PNP)2 (6 micrometer) but the Mg2+ - ATPase was unaffected by the inhibitor at concentrations as high as 28 micrometer, supporting the suggestion that the two activities represent separate enzymes. The specificity of inactivation could be demonstrated both at a physiological temperature (13 degrees C) and at 37 degrees C. The rates of inactivation were similar at both temperatures. Inactivation of the (Na+ + K+)-ATPase by (sIMP-PNP)2 was reversed by dithiothreitol, suggesting that the inhibitor forms a mixed disulfide with sulfhydryl groups on the enzyme. The inability of substrate (either ATP or its analog, adenyl-5'-yl imidodiphosphate) to protect against inactivation suggests that (sIMP-PNP)2 is reacting with sulfhydryl groups which are not associated with the active site.
These experiments compared the cardiovascular effects and the alterations in orofacial blood flow resulting from hypotension induced with sodium nitroprusside and adenosine triphosphate infusions in 30 male rats. The authors found that sodium nitroprusside did not significantly change heart rate or cardiac output, while adenosine triphosphate caused a significant decrease in heart rate associated with a small increase in cardiac output. Both hypotensive agents produced similar profound decreases in total peripheral resistance. Blood flows to orofacial structures were qualitatively similar with both agents. Both adenosine triphosphate and sodium nitroprusside caused decreased flows to the maxilla and mandible. Sodium nitroprusside increased flows to masseter and suprahyoid muscles. Adenosine triphosphate caused increased flows to suprahyoid muscles but masseter muscle flows were not significantly changed. Tongue flows responded similarly to both agents, initially decreasing, then returning to normotensive levels. Finally, sodium nitroprusside-induced hypotension was associated with the development of tachyphylaxis in some animals, whereas no similar problem was observed with use of adenosine triphosphate. The demonstration of reduced blood flows to orofacial bony structures and the absence of resistance or tachyphylaxis during adenosine triphosphate-induced hypotension support its usefulness as a hypotensive agent during orthognathic and other surgery.
Freshly secreted goat's milk contains a number of viable metabolic pathways including those for the synthesis of triglycerides and phospholipids. Toward understanding this matter, amounts of the fundamentally important energy substrate, adenosine triphosphate, in goat's milk were evaluated. Milk left in the goat udder overnight had less adenosine triphosphate (12.4 muM) than fresh secreted milk (37.6 muM). In similar experiments the skim milk derived from whole accumulating in the udder overnight was lower in adenosine triphosphate (14.2 muM) than skim milk from freshly secreted milk (26.0 muM). To determine changes in quantities of adenosine triphosphate after milking, milks were divided into two parts, one containing only milk and the other milk plus 2,4-dinitrophenol and sodium arsenate, inhibitors of oxidative and substrate level phosphorylation. Adenosine triphosphate in milk decreased during 4-h in vitro incubations, and the rate of decline was markedly greater in the presence of the inhibitors. Thus, freshly secreted goat's milk contains significant amounts of adenosine triphosphate, and more can be synthesized therein after removal from the udder. In limited samples human and bovine milks contained much lower concentrations of the compound than those in goat's milk.
The effect of adenosine triphosphate (ATP) on systemic and renal hemodynamics was studied in seven dogs anesthetized with pentobarbital and enflurane. Adenosine triphosphate was given via the vena cava, the left atrium, and the abdominal aorta close to the left renal artery. Bolus injection of ATP in the vena cava showed a dose-dependent decrease of mean arterial pressure and renal blood flow, while cardiac output showed only a slight change. Continuous infusion of ATP in the vena cava or the left atrium showed stable hypotension, decrease of renal blood flow, with slight change of cardiac output. Despite the decrease of total peripheral resistance (TRP), renal vascular resistance (RVR) increased significantly in all cases. However, the continuous infusion of ATP into the abdominal aorta close to the left renal artery caused variable responses of systemic arterial pressure and a significant decrease of the RVR. These results suggest that ATP has a renal vasodilator effect only when given directly into the renal artery, and that a renal vasoconstriction occurs responding to the systemic effect of ATP when ATP is given intravenously or into the left atrium.
PURPOSE: Inappropriate administration of intravenous verapamil to patients with wide QRS complex tachycardia due to ventricular tachycardia or atrial fibrillation with Wolff-Parkinson-White syndrome occurs frequently because of misdiagnosis, and may precipitate a cardiac arrest. We evaluated the safety and the diagnostic and therapeutic utility of adenosine triphosphate administered to a consecutive series of 34 patients during wide QRS complex tachycardia due to a variety of mechanisms. PATIENTS AND METHODS: Patients who had a hemodynamically and electrically stable, monomorphic, wide (greater than 120 msec) QRS complex tachycardia induced during an invasive cardiac electrophysiologic test were studied. Hemodynamic stability was defined by a systolic blood pressure greater than 80 mm Hg and no clinical evidence of cerebral or myocardial ischemia. Adenosine triphosphate, 20 mg, was administered as a rapid intravenous bolus via a peripheral vein during wide QRS complex tachycardia. Five surface electrocardiogram leads, at least three intracardiac electrograms, and blood pressure were monitored. RESULTS: Ventricular tachycardia was present in 14 patients (mean age 50.6 +/- 19 years, cycle length 326 +/- 67 msec) and adenosine triphosphate terminated the arrhythmia in one case. Ventricular tachycardia cycle length did not change. Among 10 patients with supraventricular tachycardia with mechanisms not involving the AV node (average ventricular cycle length 346 +/- 82 msec), one case of ectopic atrial tachycardia was terminated. The ventricular rate was transiently increased in patients with Wolff-Parkinson-White syndrome and atrial fibrillation (average R-R interval 351 +/- 84 msec in control and 317 +/- 82 msec after adenosine triphosphate, p less than 0.001). Reentrant tachycardias involving the AV node (cycle length 302 +/- 52 msec) terminated in seven of 10 patients. The drug was well tolerated, and no patient developed hemodynamic compromise necessitating cardioversion as a result of adenosine triphosphate. CONCLUSION: In the setting of electrophysiology testing, adenosine triphosphate is a safe agent, even when administered inappropriately during arrhythmias for which it is relatively ineffective, such as ventricular tachycardia, and Wolff-Parkinson-White syndrome with atrial fibrillation. It is an effective agent in terminating supraventricular tachycardia involving the AV node. Tachycardia termination following adenosine triphosphate, when used as a diagnostic test to indicate obligatory participation of the AV node, had a sensitivity of 70%, specificity of 92%, and a positive predictive accuracy of 85%. Thus, adenosine triphosphate also has diagnostic utility, but should be used after the appropriate arrhythmia diagnosis has been made based on the clinical history and analysis of the 12-lead electrocardiogram.
The central nervous system is especially vulnerable to hyperthermia-induced dysfunction, yet the mechanism for this susceptibility is poorly understood. High levels of adenosine triphosphate are necessary to maintain normal re-uptake of glutamate and aspartate, the major excitatory amino acids, by excitatory amino acid co-transporters. We hypothesized that excitotoxic neurotransmitters accumulate extracellularly when hyperthermia depletes adenosine triphosphate, leading to decreased uptake or release of excitatory amino acids by these co-transporters. Incubation of hippocampal slices at 42 degrees C, a temperature that results in coma in vivo, reduced adenosine triphosphate to 70% of control values and decreased uptake of the transportable excitatory amino acid analogue, D,L threo-beta-hydroxyaspartate, to 50% of control values. The degree of adenosine triphosphate depletion induced by hyperthermia was highly correlated with decreases in excitatory amino acid uptake. Severe adenosine triphosphate depletion (< or = 20% of control) induced by hyperthermia in combination with metabolic insults was highly correlated with the release of endogenous glutamate and aspartate. Preloading slices with excitatory amino acid analogues potentiated hyperthermia-induced alterations of excitatory amino acid transport, strongly suggesting that the hyperthermia-induced changes were largely due to altered excitatory amino acid co-transporter activity. Immunocytochemical studies suggested glutamate-like immunoreactivity was lost from axonal terminals during hyperthermia in a similar manner to losses induced by metabolic toxins. Hyperthermia due to infectious diseases or heat stroke my induce disorientation and coma. These dysfunctions may be due, in part, to altered excitatory amino acid transport induced by adenosine triphosphate depletion.
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This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocardium becomes preconditioned after the first episode of ischemia in canine models in vivo. The role of adenosine triphosphate catabolism and subsequent release of purines on reperfusion-mediated postischemic ventricular dysfunction and arrhythmias was assessed with the use of selective inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBMPR), and a specific adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA). Thirty-two anesthetized dogs were instrumented to monitor left ventricular contractility, off bypass, by sonomicrometry. During cardiopulmonary bypass dogs were treated before ischemia with either saline solution (control group, n = 8) or EHNA (100 mumol/L) and NBMPR (25 mumol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of reperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of adenosine triphosphate and induced reperfusion-mediated ventricular fibrillation and severe left ventricular dysfunction in the control group. EHNA/NBMPR treatment augmented myocardial adenosine trapping during ischemia, attenuated ventricular fibrillation, and enhanced left ventricular functional recovery, despite similar depletion of adenosine triphosphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant adenosine triphosphate depletion, ventricular fibrillation, and left ventricular stunning in both control and drug-treated groups. The prevalence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0.05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group (p < 0.05 versus control). Subsequent episodes of ischemia prevented ventricular fibrillation and did not cause cumulative left ventricular stunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adenosine triphosphate, limited purine release, and prevented ventricular fibrillation and cumulative stunning. These results suggest that intermittent ischemia and reperfusion augmented the endogenous protective mechanism or mechanisms of "preconditioning." Nucleoside trapping improved functional recovery after sustained or repetitive ischemia. It is concluded that adenosine triphosphate preservation or blockade of nucleoside transport may play an important role in the activation of endogenous myocardial protective mechanisms that "precondition" against subsequent ischemic stress.
Recovery of adenosine triphosphate after myocardial ischemia is limited by the slow adenine nucleotide de novo synthesis and the availability of precursors of the nucleotide salvage pathways. We determined the adenine nucleotide de novo synthesis in the dog by infusion of [14C]glycine and the acceleration of adenine nucleotide built up by intracoronary infusion of ribose together with [14C]glycine or radiolabeled 5-amino-4-imidazolcarboxamide riboside or adenosine in the same animal model and with the same dosage of substrates (9 mmol) in postischemic and nonischemic myocardial tissue. After 45 minutes of occlusion of a side branch of the left coronary artery, the ischemic area was reperfused for 3 hours, and needle biopsies were taken for biochemical analysis. Adenine nucleotide de novo synthesis was found to be very slow (1.5 nmol/g wet weight per hour). The rate was doubled after ischemia. Adenine nucleotide synthesis was accelerated 5-fold by ribose, the basic substrate of the adenine nucleotide de novo synthesis, 9-fold by 5-amino-4-imidazolcarboxamide riboside, an intermediate of the adenine nucleotide de novo synthesis and 90-fold by adenosine, a substrate of the nucleotide salvage pathway. Therefore, only adenosine infusion resulted in a measurable increase of adenosine triphosphate levels after 3 hours of reperfusion, but over a longer time period, ribose or 5-amino-4-imidazol-carboxamide riboside also can be expected to replenish reduced myocardial adenosine triphosphate faster than adenine nucleotide de novo synthesis. Studies with radiolabeled 5-amino-4-imidazol-carboxamide riboside showed significant incorporation of radioactivity into 5-amino-4-imidazol-carboxamide ribose triphosphate which had also risen measurably during 5-amino-4-imidazol-carboxamide ribose infusion, and which is not normally found in heart muscle.
The isolated taenia coli of the guinea pig takes up tritiated adenosine, adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate, in preference to tritiated inosine and adenine. After uptake, [(3)H]adenosine is converted and retained primarily as [(3)H]adenosine triphosphate. Tritium is released from taenia coli treated with [(3)H]adenosine upon activation of the nonadrenergic inhibitory nerves. These results are consistent with the previous evidence that adenosine triphosphate may be the transmitter from the nerves.
OBJECTIVE: The outcome of children with cyanosis after cardiac surgical procedures is inferior to that of children who are acyanotic. Animal studies indicated detrimental effects of chronic hypoxia on myocardial metabolism and function. We studied whether the presence or the degree of cyanosis adversely affected myocardial adenosine triphosphate, ventricular function, and clinical outcome in children. METHODS: Forty-eight children who underwent repair of tetralogy of Fallot were divided according to their preoperative saturation: group I, 90% to 100% (n = 14 patients); group II, 80% to 89% (n = 16 patients); and group III, 65% to 79% (n = 18 patients). Adenosine triphosphate was measured from right ventricular biopsy specimens taken before ischemia, at 15 minutes of ischemia, at end-ischemia, and at 15 minutes of reperfusion. Ejection fraction was measured by echocardiography. RESULTS: Even before surgical ischemia, compared with groups I and II, group III had lower preoperative ejection fraction (59% +/- 2.9% vs 67% +/- 1.7% and 68% +/- 1.0%; P <.01) and lower preischemic adenosine triphosphate levels (15.1 +/- 2.1 vs 19.1 +/- 1.9 and 21.4 +/- 1.5 micromol/g dry weight; P <.01). After 15 minutes of ischemia, group III had lower adenosine triphosphate levels (11.2 +/- 1.8 vs 14.77 +/- 2.3 and 17. 6 +/- 3.1 micromol/g dry weight; P <.01). With reperfusion, both cyanotic groups lost further adenosine triphosphate compared with partial recovery in the acyanotic group (-22% +/- 3.8%, -20% +/- 3. 1% vs +18% +/- 1.8%; P <.01). Children in group III had a more complicated postoperative course as evidenced by longer ventilatory support (85 +/- 25 hours vs 31 +/- 15 and 40 +/- 21 hours; P =.07), inotropic support (86 +/- 23 hours vs 38 +/- 12 and 36 +/- 4 hours; P <.01), and intensive care unit stay (160 +/- 35 hours vs 60 +/- 10 and 82 +/- 18 hours; P =.02). CONCLUSIONS: The degree of cyanosis adversely affects myocardial adenosine triphosphate, function, and clinical outcome of children who undergo cardiac operation. Children with cyanosis should be identified as a higher risk group that could be targeted for supportive interventions.
OBJECTIVE: To evaluate the in vitro effects of adenosine tryphosphate (ATP) on vasomotor tone of equine colonic vasculature. SAMPLE POPULATION: Arteries and veins from the left ventral colon of 14 mixed-breed horses euthanatized for reasons unrelated to cardiovascular or gastrointestinal tract disease. PROCEDURES: Endothelium-intact and -denuded arterial and venous rings were precontracted with 10(-7) and 1.8 x 10(-8) M endothelin-1, respectively. In 1 trial, endothelium-intact rings were also incubated with 10(-4) M N omega-nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide (NO) production. Adenosine triphosphate (10(-8) to 10(-3) M) was added in a noncumulative manner, and relaxation percentage versus time curves were generated. Areas under the curves (ie, percentage of relaxation time) were calculated. RESULTS: Relaxation response of arterial and venous rings to ATP was dose-dependent. Percentage of relaxation time in response to 10(-4) and 10(-3) MATP was significantly greater, compared with that for rings not treated with ATP Removal of endothelium attenuated but did not eliminate the relaxation response. Addition of L-NAME did not attenuate the relaxation response in arteries. At higher concentrations, the vascular response to ATP was biphasic. CONCLUSIONS AND CLINICAL RELEVANCE: ATP applied to equine colonic arterial and venous rings with and without intact endothelium induced a biphasic response characterized by transient contraction followed by slow, substantial, and sustained relaxation. This ATP-induced response is possibly mediated by a mechanism other than NO. Adenosine triphosphate may be a useful treatment to modulate colonic vasomotor tone in horses with strangulating volvulus of the ascending colon.
The adenosine triphosphatase associated with frog virus 3 shows high specificity for ATP or deoxyadenosine triphosphate and appears to be distinct from the corresponding activity in host cells, poxvirus, or reovirus. The enzyme activity is probably integrated into virus particles since it is firmly associated with subviral particles produced when approximately 50 to 60% of the outer viral protein is removed by detergent treatment. The occurrence of adenosine triphosphatase activity within three unrelated viruses suggests that adenosine tryphosphatase might be a necessary function for most viruses that replicate in the cell cytoplasm.
Adenosine triphosphate is effective in terminating re-entrant supraventricular arrhythmias, but previous studies have demonstrated a wide range for therapeutic doses. We determined dose response curves for ATP (Striadyne) in order to determine the mechanism of variability in response to this agent. In addition, this enabled comparison of AV nodal, SA nodal intraventricular and accessory pathway properties. Incremental bolus doses of ATP were administered to patients following electrophysiologic studies. Sinus node effects were determined by the change in spontaneous sinus cycle length (n = 7). AV node response was assessed by measuring the AH interval during atrial pacing at CL 400 msec (n = 7). The effects of intraventricular automaticity were assessed by observing the spontaneous cycle length (n = 1), and accessory pathway effects were observed during atrial or ventricular pacing (n = 2). ATP prolonged sinus cycle length in all patients (delta CL 295 +/- 91 msec) with a mean effective dose of 0.84 mg (range 0.5-8.0 mg). ATP prolonged AH interval with a mean effective concentration of 2.0 mg. The mean dose to produce AV block was 4.6 mg. In contrast, a ventricular escape rhythm failed to show cycle length prolongation but only showed cycle length shortening. The accessory pathways did not demonstrate block even in high doses. Thus, adenosine triphosphate selectively affects the sinoatrial node and AV nodal tissue with inhibitory effects on automaticity and conduction. The effect on intraventricular automaticity was excitatory, with minimal effects observed in accessory pathways.
Ligand binding by adenosine-triphosphate phosphoribosyltransferase was studied by different methods. 200000 daltons of enzyme bound approximately 3 molecules of histidine cooperatively with a Hill plot slope of 1.23 (half-maximal binding at 520 muM). AMP increased the affinity of the enzyme for histidine (half-maximal binding at 80 muM). In the presence of AMP the binding of histidine was strongly cooperative with a Hill plot slope of 2.3. The transferase binds a little more than 3 molecules of AMP per hexamer of enzyme with a dissociation constant of the transferase-AMP complex of approximately 25 muM. ATP was able to displace radioactive AMP from the enzyme only at a concentration ratio of 25 in favour of ATP. The transferase bound 3 molecules of ATP per 200000 daltons to an inhomogeneous population of sites, or by a mechanism of negative cooperativity. The binding of phosphoribosyladenosine triphosphate took place preferably at 1-2 sites per hexamer of enzyme, depending on several factors including the magnesium concentration.
OBJECTIVE: Ischemia is a serious problem in clinical medicine, and effective methods are needed to detect ischemia before the injury becomes irreversible. In experimental studies on several organs, PCO2 was found to increase rapidly after the onset of supply-dependent anaerobic metabolism. A shortcoming of these studies was that PCO2 was not correlated with tissue concentrations of lactate and the energy status in the cell. Thus, in this study we have measured tissue concentrations of lactate, phosphocreatine, and adenosine triphosphate. We hypothesized that during ischemic conditions, PCO2 reflects lactate generation in the cell and not exhausted energy stores per se. If this is the case, PCO2 can be used to detect ischemia before the energy stores are depleted. Consequently, therapy can be instituted at a time when the organ is salvageable. DESIGN: Prospective laboratory study. SETTING: University research laboratory. SUBJECTS: Seven pigs. INTERVENTIONS: In a porcine model, gluteal skeletal muscles with no-flow ischemia were examined. PCO2 was measured both in situ and in vitro at increasing periods of time. Concomitantly, tissue lactate, adenosine triphosphate, and phosphocreatine were analyzed. MEASUREMENTS AND MAIN RESULTS: Tissue surface CO2 tension (PtCO2) increased rapidly after onset of ischemia. From a baseline of 63 +/- 3 torr (8.4 +/- 1.2 kPa) under aerobic conditions, it increased to 157 +/- 6 torr (21 +/- 2.2 kPa) after 30 mins of ischemia and 386 +/- 9 torr (51.5 +/- 3 kPa) at 120 mins. The rapid increase of PtCO2 correlated well with increasing values of lactate (r2 >.9) in the tissue. Adenosine triphosphate was essentially unchanged for 45 mins after onset of ischemia, after which it declined. Phosphocreatine decreased earlier than adenosine triphosphate in accordance with the notion that high-energy phosphate groups are transferred from phosphocreatine to adenosine triphosphate. CONCLUSION: In this porcine model of skeletal muscle ischemia, PtCO2 correlates well with tissue lactate and increases long before the energy stores of phosphocreatine and most notably adenosine triphosphate are severely reduced. Thus, PtCO2 could be monitored to detect and treat earlier stages of ischemia.