ATP Infusion Research Articles

K+ as a vasodilator in resting human muscle: implications for exercise hyperaemia

Potassium (K(+)) released from contracting skeletal muscle is considered a vasodilatory agent. This concept is mainly based on experiments infusing non-physiological doses of K(+). The aim of the present study was to investigate the role of K(+) in blood flow regulation. We measured leg blood flow (LBF) and arterio-venous (A-V) O(2) difference in 13 subjects while infusing K(+) into the femoral artery at a rate of 0.2, 0.4, 0.6 and 0.8 mmol min(-1). The lowest dose increased the calculated femoral artery plasma K(+) concentration by approx.1 mmol L(-1). Graded K(+) infusions increased LBF from 0.39 +/- 0.06 to 0.56 +/- 0.13, 0.58 +/- 0.17, 0.61 +/- 0.11 and 0.71 +/- 0.17 L min(-1), respectively, whereas the leg A-V O(2) difference decreased from 74 +/- 9 to 60 +/- 12, 52 +/- 11, 53 +/- 9 and 45 +/- 7 mL L(-1), respectively (P < 0.05). Mean arterial pressure was unchanged, indicating that the increase in LBF was associated with vasodilatation. The effect of K(+) was totally inhibited by infusion (27 micromol min(-1)) of Ba(2+), an inhibitor of Kir2.1 channels. Simultaneous infusion of ATP and K(+) evoked an increase in LBF equalled to the sum of their effects. Physiological infusions of K(+) induce significant increases in resting LBF, which are completely blunted by inhibition of the Kir2.1 channels. The present findings in resting skeletal muscle suggest that K(+) released from contracting muscle might be involved in exercise hyperaemia. However, the magnitude of increase in LBF observed with K(+) infusion suggests that K(+) only accounts for a limited fraction of the hyperaemic response to exercise.

Difference in Myocardial Flow Reserve Between Patients With Dilated Cardiomyopathy and Those With Dilated Phase of Hypertrophic Cardiomyopathy Evaluation by 15O-Water PET

The clinical features of patients with the dilated phase of hypertrophic cardiomyopathy (DHCM) may resemble those of patients with dilated cardiomyopathy (DCM); that is, systolic dysfunction and left ventricular dilatation. Myocardial flow reserve (MFR) is impaired in patients with nonischemic cardiomyopathy, and the reduced MFR may be related to poor prognosis. Several studies report that the mortality rate for patients with DHCM is higher than for DCM, but the difference between these 2 cardiomyopathies is still unclear. The purpose of this study was to assess the MFR of these 2 cardiomyopathies, using (15)O-water positron emission tomography (PET) to elucidate their differences. In total 30 patients were investigated: 23 with DCM (Group A) and 7 with DHCM (Group B). All those who were in a stable condition underwent cardiac catheterization. Myocardial blood flow (MBF) at rest and under ATP infusion was measured by (15)O-water PET, and the MFR was calculated. There were no significant differences in the hemodynamics of the 2 groups. The mean MFR in DHCM was significantly lower than that in DCM (1.49+/-0.31 vs 2.62+/-1.08; p=0.042), whereas MBF at rest did not differ (DCM vs DHCM: 0.66+/-0.20 vs 0.49+/-0.05 ml . min(-1) . g(-1); NS). The MFR in both Group A and B was significantly decreased compared with the normal controls (MFR in normal controls: 5.15+/-1.64, p=0.00015, 0.00013, respectively). These results suggest that impaired vasodilatation (ie, dysfunction of the microcirculation) is more severe in patients with DHCM than in patients with DCM, even though patients' characteristics and hemodynamics do not differ.

Noninvasive Visualization and Measurement of Middle Cardiac Vein Flow by Transthoracic Doppler Echocardiography

Transthoracic Doppler echocardiography offers a noninvasive approach for imaging posterior descending coronary artery (PD) running in the posterior longitudinal sulcus along the middle cardiac vein (MCV). To evaluate whether the MCV flow velocity reserve can reflect the PD flow reserve, 22 children with various heart diseases were examined using transthoracic Doppler echocardiography. Introduction of a modified transthoracic two chamber view with the transducer rotated counterclockwise and angulated posteriorly allows visualization of the MCV and PD. Peak systolic flow velocity and average peak systolic flow velocity in the MCV and peak diastolic flow velocity and average peak diastolic flow velocity in the PD were measured at rest and hyperemic conditions (intravenous administration of adenosine of 0.16 mg/kg/min). Coronary flow reserve was defined as the ratio of peak hyperemic to basal average peak flow velocity. ATP infusion induced significant increases in the peak systolic flow velocity and average peak systolic flow velocity in the MCV. The mean MCV flow velocity reserve in the patients was 1.94 +/- 0.44. Significant increases in the peak diastolic flow velocity and the average peak diastolic flow velocity in the PD were also observed during ATP infusion, and the mean PD flow velocity reserve (2.19 +/- 0.62) was significantly higher than the GCV flow velocity reserve (p < 0.0001). There was a good correlation between the MCV flow velocity reserve and PD flow velocity reserve (r = 0.86, p < 0.0001). This study demonstrated that it was possible to measure the MCV flow velocity and MCV flow velocity reserve in pediatric patients by transthoracic Doppler echocardiography. The MCV flow reserve correlated highly with the PD flow reserve. However, the degree of the MCV flow during hyperemia was less than that of the PD flow. This underestimation should be considered when the reactive hyperemic response is evaluated from the MCV flow velocity.

ATP Induces Sustained Facilitation of Craniofacial Nociception Through p2x Receptors on Neck Muscle Nociceptors in Mice

Noxious input from neck muscles probably plays a key role in tension-type headache pathophysiology. ATP selectively excites group III and IV muscle afferents in vitro. Accordingly, ATP infusion into trapezius muscle induces strong pain and local tenderness in healthy man. The present study addresses the impact of ATP on neck muscle nociception in anaesthetized mice. Craniofacial nociceptive processing was tested by the jaw-opening reflex via noxious electrical tongue stimulation. Within 2 h after injection of 100 nmol/l or 1 micromol/l ATP into semispinal neck muscles, reflex integrals significantly increased by 114% or 328%, respectively. Preceding intramuscular administration of the P2X receptor antagonist PPADS (3-100 nmol/l) suppressed the ATP effect. Subsequent application of PPADS (100 nmol/l) caused a total recovery of facilitated reflex to baseline values. ATP induces sustained facilitation of craniofacial nociception by prolonged excitation of P2X receptors in neck muscles.

Central hemodynamics with ATP and Kicking Exercise Mediated Increases in Leg Blood Flow

Graded intrafemoral artery infusion of ATP produces increases in leg blood flow (LBF) that are similar to those induced by incremental leg-kicking and cycling exercise. Whether ATP infusion mimics the exercise central hemodynamics, despite the absence of the muscle pump not increasing venous return, has not been investigated. PURPOSE: To determine whether the central hemodynamic changes induced by intrafemoral artery ATP infusion were similar to those produced by dynamic one-legged kicking exercise. METHODS: 7 healthy volunteer men performed three-minute bouts of one-legged kicking exercise at 25%, 50%, 75% and 100% of their peak power. ATP was infused into their femoral artery at 1, 4, 16 and 64 umol/min, in doses chosen to match the LBF response to the progressive increase in exercise intensity while seated upright. Mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), stroke volume (SV) and cardiac output (CO) were obtained at rest and during each stage of exercise and ATP infusion. RESULTS: There was no difference in the LBF response to leg kicking exercise and its matched ATP infusion increases. There was no significant difference in CVP and CO between ATP infusion and leg kicking exercise (CO increases from rest (P<0.05) ranging from ∼7 L/min to ∼15 L/min). However, HR was increased 44 ± 4% by ATP, P<0.001, and by 118 ± 9% by KE, P<0.001; SV was increased 51 ±4% by ATP, P<0.001, and only 9 ± 4% by KE, P<0.06; and MAP was decreased 8 ± 4% by ATP, P>0.05, and was increased 58 ±8% by KE, P<0.05. CONCLUSION: These results indicate that intrafemoral artery ATP infusion can match the CO response to one-legged kicking exercise, by mainly elevating SV. This suggests that the activation of the muscle pump is not essential to increase venous return and CO during small muscle mass exercise in humans. Supported by the Novo Nordisk Foundation

Effects of ATP-induced leg vasodilation on V̇o2 peak and leg O2 extraction during maximal exercise in humans

During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.

PI-16An intrapatient dose escalation and tolerability study of adenosine triphosphate infusions on a weekly schedule for eight weeks in patients with advanced solid tumors

BACKGROUND ATP is an endogenous nucleotide. Preliminary data suggested that exogenous ATP may improve cachexia in advanced cancer patients. The major objectives of this study were to determine the tolerable dose of a weekly infusion of ATP, within the planned dose range and to investigate its effects cancer cachexia biomarkers. METHODS This study was an open label intra-patient dose escalation study. Cancer patients with advanced stage solid tumors received an 8 hour iv infusion of ATP weekly for 8 weeks at a starting dose of 50 mcg/kg/min, escalating to 75 and then 100 mcg/kg/min, if tolerated. Clinical and laboratory toxicity, ATP pharmacokinetics and biomarkers for cachexia were monitored. RESULTS Fifteen (9M:6F) pts. median age 63y (range 38–80) entered the study. ATP was tolerated by 15/15 pts. at 50 mcg/kg/min and by 12/12 pts. who received 100 mcg/kg/min. No patient developed grade III/IV dose limiting toxicity. Common toxicities were chest tightness/dyspnea, without EKG changes (60%); sinus tachycardia (40%) and were more frequent at the highest ATP dose. Two patients had transient, asymptomatic 3rd degree AV block (grade I). ATP Cmax increased post infusion (ANOVA p =.01). Karnofsky score, weight, percent body fat, muscle strength and prealbumin concentration decreased (all p< 0.05) and CRP, IL-6 increased (p< 0.05) with treatment. CONCLUSIONS In this Phase I study the tolerated ATP dose was 100 mcg/kg/min for 8h / week, and the biomarkers for cancer cachexia did not improve with treatment. Clinical Pharmacology & Therapeutics (2005) 79, P11–P11; doi: 10.1016/j.clpt.2005.12.037

Role of Purinoceptors in Cardiac Function in Rats during Ontogeny

Intravenous injection of exogenous ATP (10(-4) M) to rats aging 21, 56, and 100 days increased the heart rate by the 15th sec postinjection. Stable ATP analogue alpha,beta-methylene-ATP in an equimolar concentration increased the heart rate in rats aging 56 and 100 days (by the 15th second after treatment), but had no effect on 21-day-old animals. alpha,beta-Methylene-ATP in a concentration of 10(-7) M increased the heart rate in 21-day-old rat pups, which attests to high sensitivity of P2 purinoceptors. Administration of ATP and alpha,beta-methylene-ATP after treatment with nonselective purinoceptor antagonist suramin did not increase the heart rate in rats of different age groups. Infusion of ATP and its stable analogue after administration of selective P2Y receptor antagonist reactive blue 2 increased the heart rate in rats of different age groups. These changes reflect activation of P2X receptors in the heart.

Neurohormones and Cytokines in Heart Failure. Correlation With Coronary Flow Reserve

In heart failure, the coronary flow reserve (CFR) measured by positron-emission tomography (PET) is reduced. As neurohormone and cytokine levels are also altered in patients with the condition, our aim was to determine whether there is a correlation between CFR and neurohormone and cytokine levels. The study included 40 patients with heart failure but without ischemic heart disease. Myocardial blood flow was measured by PET using nitrogen-13 ammonia at baseline and during ATP infusion. The CFR was calculated for each patient. In addition, levels of the following were determined: norepinephrine, endothelin-1, angiotensin-II, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), tumor necrosis factor-alpha, interleukin (IL)-1beta, soluble IL-2 receptor, and IL-6. All neurohormone levels were elevated above reference values. The levels of all cytokines, except IL-1beta, were also elevated. There was a significant negative correlation between CFR and the levels of several neurohormones: ANP (r=-0.476), BNP (r=-0.442), and IL-6 (r=-0.509). In heart failure, the decrease in CFR is correlated with increases in the levels of certain neurohormones (i.e., ANP and BNP) and cytokines (i.e., IL-6), with vasodilatory effect. These increases are probably are related to compensatory mechanisms that are unable to correct for the endothelial dysfunction present in these patients.

Sinus slowing caused by adenosine-5′-triphosphate in patients with and without sick sinus syndrome under various autonomic states

Adenosine infusion can potentially be used as a diagnostic test for sick sinus syndrome (SSS) based on its negative chronotropic effects. Whether autonomic tone underlies adenosine’s negative chronotropic effects remains unknown. This study was to investigate the bradycardiac response of sinus node to ATP in patients with and without clinical SSS by measuring atrial cycle length (ACL) before and after bolus of ATP in different states of autonomic tone. The negative chronotropic effect of ATP was assessed by comparing the mean ACL before ATP administration with the longest ACL after a bolus of ATP infusion (ΔACL). Our results showed that ΔACL in patients with SSS were significantly greater than that without SSS ( P<.001) in all 4 states, and IHR in patients with SSS were significantly lower than calculated IHR ( P<.0001). Moreover, there was no significant difference in ΔACL between the 4 states in patients with SSS ( P = .99). However, ΔACL was significantly greater during isoproterenol infusion and after propranolol administration in patients without sinus node dysfunction, comparing with baseline state ( P<.01), but not after combination of atropine ( P = .33). Our results indicate that the negative chronotropic effect of ATP on sinus node is much more dramatic in patients with SSS, in which the intrinsic disease of sinus node is responsible for the abnormal adenosine-mediated sinus arrest, and this effect is influenced by autonomic tone in patients without sinus node dysfunction but not in patients with SSS.

Extracellular ATP activates c-jun N-terminal kinase signaling and cell cycle progression in hepatocytes.

Partial hepatectomy leads to an orchestrated regenerative response, activating a cascade of cell signaling events necessary for cell cycle progression and proliferation of hepatocytes. However, the identity of the humoral factors that trigger the activation of these pathways in the concerted regenerative response in hepatocytes remains elusive. In recent years, extracellular ATP has emerged as a rapidly acting signaling molecule that influences a variety of liver functions, but its role in hepatocyte growth and regeneration is unknown. In this study, we sought to determine if purinergic signaling can lead to the activation of c-jun N-terminal kinase (JNK), a known central player in hepatocyte proliferation and liver regeneration. Hepatocyte treatment with ATPgammaS, a nonhydrolyzable ATP analog, recapitulated early signaling events associated with liver regeneration-that is, rapid and transient activation of JNK signaling, induction of immediate early genes c-fos and c-jun, and activator protein-1 (AP-1) DNA-binding activity. The rank order of agonist preference, UTP>ATP>ATPgammaS, suggests that the effects of extracellular ATP is mediated through the activation of P2Y2 receptors in hepatocytes. ATPgammaS treatment alone and in combination with epidermal growth factor (EGF) substantially increased cyclin D1 and proliferating cell nuclear antigen (PCNA) protein expression and hepatocyte proliferation in vitro. Extracellular ATP as low as 10 nM was sufficient to potentiate EGF-induced cyclin D1 expression. Infusion of ATP by way of the portal vein directly activated hepatic JNK signaling, while infusion of a P2 purinergic receptor antagonist prior to partial hepatectomy inhibited JNK activation. In conclusion, extracellular ATP is a hepatic mitogen that can activate JNK signaling and hepatocyte proliferation in vitro and initiate JNK signaling in regenerating liver in vivo. These findings have implications for enhancing our understanding of novel factors involved in the initiation of regeneration, liver growth, and development.

Promising effects of adenosine triphosphate infusion on nutritional status and quality of life in advanced non‐small‐cell lung cancer: a randomized clinical trial

AbstractPrevious studies animal and phase I/II studies suggested that regular ATP infusions may inhibit loss of body weight in cancer. In this report, we summarize data from a recent trial (Agteresch et al. [2000a] J Natl Cancer Inst 92:321–328; Agteresch et al. [2000b] Eur J Clin Pbarmacol 56:49–55) in 58 patients with non‐small‐cell lung cancer, stage IIIB or IV. Patients were randomized to receive either 10 intravenous 30‐h ATP infusions every 2 to 4 weeks (n=28), or no ATP (n=30). Body weight, body composition (anthropometry, isotope dilution), muscle strength (elbow flexor and knee extensor), energy intake (3‐day food record), and quality of life (validated Rotterdam Symptom Checklist, RSCL) were assessed at 4‐week intervals during 28 weeks. Between‐group differences were tested for statistical significance (P &lt; 0.05) by repeated‐measures analysis of covariance. Over the 28‐week follow‐up period, the control group showed progressive deterioration in body weight, fat mass, body cell mass, arm muscle area, and elbow flexor and knee extensor muscle strength. In contrast, in the ATP group, complete stabilization of these parameters was observed. Energy intake decreased significantly in the control group, but remained stable in the ATP group. ATP also inhibited the progressive rise in plasma values of C‐reactive protein seen in control patients. All mentioned between‐group differences were statistically significant. Significant favorable effects of ATP were also found for different domains of quality of life as assessed by the RSCL, i.e., physical, functional, and overall quality of life, whereas no significant effect of ATP on the psychological subscale of the RSCL was detected. In conclusion, ATP is the first agent that has been shown, in a randomized clinical trial, to counteract the loss of both metabolically active tissues (skeletal muscle and body cell mass) and fat mass, and improve muscle strength and quality of life (including functional status and fatigue) in patients with advanced cancer. Maintenance of energy intake and inhibition of chronic inflammation are likely to contribute to these effects of ATP. These results warrant further studies in patients with cancer and inflammatory diseases. Drug Dev. Res. 59:146–151, 2003. © 2003 Wiley‐Liss, Inc.

Adenosine triphosphate infusion increases liver energy status in advanced lung cancer patients: An in vivo31P magnetic resonance spectroscopy study

We recently observed inhibition of weight loss in patients with advanced nonsmall-cell lung cancer after intravenous infusion of ATP. Because liver ATP levels were found to be decreased in lung cancer patients with weight loss, the present 31P magnetic resonance spectroscopy (MRS) study was aimed at investigating whether ATP infusion restores liver energy status in these patients. Nine patients with advanced nonsmall-cell lung cancer (stage IIIB/IV) were studied 1 week before (baseline) and at 22 to 24 hours of continuous ATP infusion (37-75 μg/kg/min). Localized hepatic 31P MR spectra (repetition time 15 seconds), obtained in the overnight-fasted state, were analyzed for ATP and Pi content. Ten healthy subjects (without ATP infusion) served as control. Liver ATP levels in lung cancer patients increased from 8.8 ± 0.7% (relative to total MR-detectable phosphate; mean ± SE) at baseline to 12.2 ± 0.9% during ATP infusion (P < .05), i.e., a level similar to that in healthy subjects (11.9 ± .9%). The increase in ATP level during ATP infusion was most prominent in patients with ≥5% weight loss (baseline: 7.9 ± 0.7%, during ATP infusion: 12.8 ± 1.0%, P < .01). In conclusion, ATP infusion restores hepatic energy levels in patients with advanced lung cancer, especially in weight-losing patients. These changes may contribute to the previously reported beneficial effects of ATP infusion on the nutritional status of lung cancer patients. (HEPATOLOGY .)

ATP-mediated release of arachidonic acid metabolites from venular endothelium causes arteriolar dilation.

This study was designed to test the hypothesis that venular administration of ATP resulted in endothelium-dependent dilation of adjacent arterioles through a mechanism involving cyclooxygenase products. Forty-three male golden hamsters were anesthetized with pentobarbital sodium (60 mg/kg ip), and the cremaster muscle was prepared for in vivo microscopy. ATP (100 microM) injected into venules dilated adjacent arterioles from a mean diameter of 51 +/- 4 to 76 +/- 6 microm (P < 0.05, n = 6). To remove the source of endothelial-derived relaxing factors, the venules were then perfused with air bubbles to disrupt the endothelium. Resting arteriolar diameter was not altered after disruption of the venular endothelium (51 +/- 5 microm), and the responses to venular ATP infusions were significantly attenuated (59 +/- 4 microm, P < 0.05). To determine whether the relaxing factor was a cyclooxygenase product, ATP infusion studies were repeated in the absence and presence of indomethacin (28 microM). Under control conditions, ATP (100 microM) infusion into the venule caused an increase in mean arteriolar diameter from 55 +/- 4 to 78 +/- 3 microm (P < 0.05, n = 6). In the presence of indomethacin, mean resting arteriolar tone was not significantly altered (49 +/- 4 microm), and the response to ATP was significantly attenuated (54 +/- 4 microm, P < 0.05, n = 6). These studies show that increases in venular ATP concentrations stimulate the release of cyclooxygenase products, possibly from the venular endothelium, to vasodilate the adjacent arteriole.

Extracellular Nucleotides ATP and UTP Induce a Marked Acute Release of Tissue-type Plasminogen Activator In Vivo in Man

Extracellular nucleotides such as ATP and UTP are released by activation of platelets and ischemic tissue injury. The aim of the present study was to investigate whether ATP and UTP can induce acute tPA release from the vascular endothelium in vivo. Nine healthy subjects were studied in a perfused-forearm model during stepwise intraarterial infusions of ATP and UTP (10-200 nmol/min), and UTP during inhibition of prostanoid and NO synthesis by indomethacin and L-NMMA. ATP and UTP induced a similar and marked stimulation of forearm tPA release which increased 11- and 18-fold above baseline (p < or =0.01 for both) in conjunction with pronounced vasodilation. Neither the acute tPA release nor the vasodilation could be abrogated by NO and prostanoid synthesis inhibition. The similar effect of ATP and UTP suggests that P2Y rather than adenosine receptors mediate the response. Release of extracellular nucleotides in ischemic tissue may induce a pronounced activation of the endogenous fibrinolytic system.

Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer

Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer

Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer

Cancer cachexia is associated with elevated lipolysis, proteolysis and gluconeogenesis. ATP infusion has been found to significantly inhibit loss of body weight, fat mass and fat-free mass in patients with advanced lung cancer. The present study was aimed at exploring the effects of ATP on whole-body glucose turnover, alanine turnover and gluconeogenesis from alanine. Twelve patients with advanced non-small-cell lung cancer (NSCLC) were studied 1 week before and during 22-24 h of continuous ATP infusion. After an overnight fast, turnover rates of glucose and alanine, and gluconeogenesis from alanine, were determined using primed constant infusions of ¿6, 6-(2)H(2)ğlucose and ¿3-(13)Călanine. Thirteen NSCLC patients and eleven healthy subjects were studied as control groups without ATP infusion. During high-dose ATP infusion (75 microg.min(-1).kg(-1)), glucose turnover was 0.62+/-0.07 mmol.h(-1).kg(-1), compared with 0. 44+/-0.13 mmol.h(-1).kg(-1) at baseline (P=0.04). For gluconeogenesis a similar, but non-significant, trend was observed ¿baseline, 0.30+/-0.16 mmol.h(-1).kg(-1); during ATP, 0.37+/-0.13 mmol.h(-1).kg(-1) (P=0.08). At lower ATP doses (37-50 microg. min(-1).kg(-1)) these effects were not detected. The relative increase in glucose turnover during ATP infusion compared with baseline showed a significant correlation with the ATP dose (r=0.58, P=0.02). No change in alanine turnover was observed at any ATP dose. The results of this study indicate an increase in glucose turnover during high-dose ATP infusion compared with baseline levels. During high-dose ATP infusion, glucose turnover was similar to that during low-dose ATP infusion and to that in control NSCLC patients. Between ATP infusions, however, glucose turnover in patients treated with high-dose ATP was significantly lower than that in the low-dose and control NSCLC patients (P=0.04 and P=0.03 respectively), and similar to that in healthy subjects. This would suggest that repeated high-dose ATP infusions may inhibit glucose turnover between infusion periods.

Aggravation of chemically-induced injury in perfused rat liver by extracellular ATP

The effects of purinergic receptor agonists on acute liver damage and hemodynamics were studied using chemically-induced liver injury. Rat livers were perfused in situ 24 h after treatment with D-galactosamine (800 mg/kg, i.p.). In these livers, infusion of ATP (50 μM) into the portal vein caused a rapid increase in the leakage of LDH and AST from perfused liver in a dose dependent manner, accompanied with flow reduction. The similar but less effective responses were also observed by the infusion of ADP. Infusion of adenosine, a P 1-receptor agonist, induced only minimal changes of liver damage and flow rate. The ATP-induced changes were almost completely suppressed by P 2-receptor antagonist, suramin, but not affected by P 1-receptor antagonist, 8-phenyltheophylline. Pretreatment of rats with gadolinium chloride, which depletes Kupffer cells, did not inhibit the potentiation of liver damage caused by ATP, whereas hemodynamic effects of ATP were significantly attenuated by gadolinium. These results indicate that extracellular ATP aggravates acute liver injury mediated by P 2-type purinergic receptors.

ATP infusion boosts health in NSCLC

ATP infusion boosts health in NSCLC

Effect of regional hyperemia on myocardial uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose.

2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) may be used to predict glucose kinetics when the factor relating differences in transport and phosphorylation between compounds remains constant ("lumped constant"). It is not clear whether hyperemia alters that factor. In anesthetized swine, myocardial FDG uptake was estimated by positron emission tomography, during an intracoronary infusion of either adenosine, ATP, or bradykinin (40 microg x kg(-1) x min(-1), 40 microg x kg(-1) x min(-1), and 2 nmol x kg(-1) x min(-1), respectively; n = 6 for all groups). In controls during normal perfusion (n = 6), FDG uptake was 0.78 +/- 0.32 micromol x g(-1) x min(-1), whereas glucose uptake by Fick was 0.71 +/- 0.25 micromol x g(-1) x min(-1) (r = 0.73; P < 0.05). Adenosine increased blood flow from 1.29 +/- 0.43 to 4.80 +/- 2.19 ml x g(-1) x min(-1) (P < 0.05) and glucose uptake from 1.16 +/- 1.10 to 3.35 +/- 2.12 micromol x g(-1) x min(-1) (P < 0.05), whereas FDG uptake in the hyperemic region was lower than remote regions (0.46 +/- 0.29 and 0.95 +/- 0.55 micromol x g(-1) x min(-1), respectively; P < 0.05). In the ATP and bradykinin groups, blood flow increased four- and twofold, respectively, with no net change in glucose uptake. FDG uptake in the hyperemic region was also significantly lower than remote regions. For all animals, the ratio of blood flow in the hyperemic region relative to remote region was inversely proportional to the ratio of FDG uptake in the same regions (r(2)=0.73; P < 0.001). Because nitric oxide elaboration during hyperemia could potentially alter substrate preference and FDG kinetics, six additional swine were studied during maximal adenosine before and after intracoronary N(G)-monomethyl-L-arginine (1.5 mg/kg). Inhibition of nitric oxide had no effect on either regional myocardial substrate uptake or FDG accumulation. In conclusion, hyperemia decreased regional myocardial FDG uptake relative to normally perfused regions and this effect on the lumped constant was independent of nitric oxide.