Adenosine Triphosphate Infusion Research Articles

Application of adenosine 5'-triphosphate (ATP) infusions in palliative home care: design of a randomized clinical trial.

BackgroundPalliative care in cancer aims at alleviating the suffering of patients. A previous study in patients with advanced non-small-cell lung cancer showed that adenosine 5'-triphosphate (ATP) infusions had a favourable effect on fatigue, appetite, body weight, muscle strength, functional status and quality of life. The present study was designed 1. To evaluate whether ATP has favourable effects in terminally ill cancer patients, 2. To evaluate whether ATP infusions may reduce family caregiver burden and reduce the use of professional health care services, and 3. To test the feasibility of application of ATP infusions in a home care setting.Methods/DesignThe study can be characterized as an open-labelled randomized controlled trial with two parallel groups. The intervention group received usual palliative care, two visits by an experienced dietician for advice, and regular ATP infusions over a period of 8 weeks. The control group received palliative care as usual and dietetic advice, but no ATP. This paper gives a description of the study design, selection of patients, interventions and outcome measures.DiscussionFrom April 2002 through October 2006, a total of 100 patients have been randomized. Follow-up of patients will be completed in December 2006. At the time of writing, five patients are still in follow up. Of the 95 patients who have completed the study, 69 (73%) have completed four weeks of follow-up, and 53 (56%) have completed the full eight-week study period. The first results are expected in 2007.

Combined inhibition of NO, prostaglandins and EDHFs inhibits ATP‐induced vasodilation in the human leg

Adenosine-5′-triphosphate (ATP) can bind to P2y-purinergicreceptors and induce vasodilation in skeletal muscle, but the precise mechanisms by which this occurs remain unclear. To investigate whether ATP induced vasodilation is mediated by the action of nitric oxide (NO), prostaglandins and/or endothelial-derived hyperpolarizing factors (EDHFs), we measured leg hemodynamics before and during 5 min of intra-arterial infusion of ATP (0.41±0.04μmol min−1;mean±SEM) in 8 healthy, male subjects (24±2 years, 76±3 kg) with and without co-infusion of indomethacin (INDO; 621±17 μg min−1), NG-mono-methyl-L-arginine (L-NMMA; 12.4±0.3 mg min−1), tetraethylammonium chloride (TEA; 12.4±0.3 mg min−1) or INDO + L-NMMA + TEA. Basal leg blood flow (LBF) was 0.46±0.06 l min−1, but was lower with either L-NMMA (0.32±0.03) or all three inhibitors (0.28±0.06)(P<0.05), whereas infusion of either TEA or INDO had no effect on basal flow. ATP infusion increased LBF to 2.4±0.2 l min−1, but with co-infusion of either INDO or L-NMMA alone, or all three inhibitors combined, it was 13±8, 22±8 and 39±5 % lower, respectively, than with ATP infusion alone. Infusion of TEA did not alter the ATP induced hyperemia. The lower LBF with ATP combined with INDO, L-NMMA and triple blockade was associated with a 8–12% higher blood pressure and a 15–45 % lower vascular conductance, while heart rate and leg VO2 remained similar. These results indicate that both NO and prostaglandins play an important role in ATP mediated vasodilatation, whereas EDHFs appear to be less important. Supported by Lundbeck Foundation

Diurnal Variation in Coronary Flow Velocity Reserve in Healthy Men

Background. A number of cardiovascular diseases show diurnal variation. However, it is unknown whether coronary circulation exhibits diurnal variation.Methods. The flow velocities in the left anterior descending coronary artery of 15 healthy men were measured by transthoracic Doppler echocardiography both at rest and during intravenous infusion of adenosine triphosphate at 7 AM, noon, 5 PM and 9 PM. Coronary flow velocity reserve (CFVR) was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR at 7 AM was significantly smaller than that at 9 PM (p=0.001; 7 AM, 3.23 ± 0.66; noon, 3.89 ± 0.86; 5 AM, 3.46 ± 0.65; 9 PM, 4.41 ± 1.11, respectively). CFVR at 5 PM was also significantly smaller than that at 9 PM (p=0.008).Conclusions. Diurnal variation in CFVR exists in healthy men. This finding may be related to the diurnal variation in cardiovascular events.

Cibenzoline improves coronary flow velocity reserve in patients with hypertrophic obstructive cardiomyopathy

The effect of cibenzoline, a class-Ia antiarrhythmic drug, on coronary flow velocity reserve (CFVR) was examined in patients with hypertrophic cardiomyopathy using transthoracic Doppler echocardiography. Coronary flow velocity reserve was assessed in 11 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 12 patients with hypertrophic nonobstructive cardiomyopathy (HNCM), before and after the intravenous administration of cibenzoline (1 mg/kg). Coronary hyperemia was induced by an intravenous infusion of adenosine triphosphate and CFVR was calculated as the ratio of hyperemic to basal mean coronary diastolic flow velocity. At baseline, CFVR was significantly correlated with left ventricular outflow tract pressure gradient (LVPG) in patients with HOCM (r = 0.67, P < 0.03). In patients with HOCM, administration of cibenzoline significantly improved impaired CFVR (2.0 +/- 0.8 to 3.0 +/- 1.0, P < 0.001), and reduced LVPG (55 +/- 30 to 23 +/- 18 mmHg, P < 0.001), while CFVR remained unchanged in patients with HNCM (2.6 +/- 0.9 to 2.9 +/- 0.8, P not significant). Cibenzoline not only reduces LVPG but also improves CFVR in patients with HOCM. In addition left ventricular outflow obstruction plays an important role in impaired coronary circulation in patients with HOCM.

Effects of ATP on rat renal haemodynamics and excretion: role of sodium intake, nitric oxide and cytochrome P450

Adenosine-5'-triphosphate (ATP) affects intrarenal vascular tone and tubular transport via P2 receptors; however, the actual role of the system in regulation of renal perfusion and excretion remains unclear and is the subject of this whole-kidney study. Effects of suprarenal aortic ATP infusion, 0.6-1.2 mg kg(-1) h(-1), were examined in anaesthetised rats maintained on low- (LS) or high-sodium (HS) diet. Renal artery blood flow (RBF, transonic flow probe) and the perfusion (laser-Doppler flux) of the superficial cortex (CBF) and outer and inner medulla (OM-BF, IM-BF) were measured, together with sodium and water excretion and urine osmolality. Adenosine-5'-triphosphate did not change arterial pressure, RBF or CBF while the effects on medullary perfusion depended on sodium intake. In LS rats ATP increased IM-BF 19 +/- 6%, the effect was prevented by inhibition of nitric oxide (NO) with N-nitro-l-arginine methyl ester. In HS rats ATP decreased OM-BF 16 +/- 3% and IM-BF (7 +/- 4%, not significant); previous inhibition of cytochrome P450 with 1-aminobenzotriazol blunted the OM-BF decrease and reversed the previous decrease of IM-BF to a 13 +/- 8% increase. Inhibition of P2 receptors with pyridoxal derivative (PPADS) abolished medullary vascular responses to ATP. In HS rats pre-treated with PPADS, ATP increased tubular reabsorption, probably via adenosine formation and stimulation of P1 receptors. The data indicate a potential role of ATP in the selective control of renal medullary perfusion, different in sodium depleted and sodium replete rats. The action of ATP appears to be mediated by the NO system and the cytochrome P450 dependent vasoactive metabolites.

Direct comparison of adenosine and adenosine 5′-triphosphate as pharmacologic stress agents in conjunction with Tl-201 SPECT: Hemodynamic response, myocardial tracer uptake, and size of perfusion defects in the same subjects

Adenosine 5'-triphosphate (ATP), a potent and inexpensive coronary vasodilator, was introduced as a pharmacologic stress agent for thallium 201 single photon emission computed tomography (SPECT). However, there has been no direct comparison of ATP and adenosine as myocardial stressors in the same subjects. Thirty-six patients underwent consecutive Tl-201 SPECT imaging with adenosine and ATP in a randomly assigned order. There were no changes in clinical status and no invasive procedures were performed between the two tests. The hemodynamic response and side effects were monitored, and myocardial tracer uptake was assessed by use of a visual grading system and quantitative analysis via a CEqual map. The hemodynamic changes and adverse effects did not differ significantly between the two groups. There were no changes in the detection of any perfusion defect on a per-subject basis, except in one. The exact agreement rate for the visual grading of the myocardial tracer uptake was 84.8%. However, the average extent of the perfusion defect and the severity score were higher with adenosine. The hemodynamic changes and the degree of myocardial uptake were similar between the adenosine and ATP infusion. However, quantitative analysis by use of a CEqual map revealed smaller perfusion defects and lower severity scores in subjects undergoing Tl-201 SPECT with ATP.

Myocardial perfusion imaging with adenosine triphosphate predicts the rate of cardiovascular events

Adenosine triphosphate (ATP) has effects similar to adenosine, including a very short half-life, with the advantage of a much lower cost. Our aim was to evaluate whether myocardial single photon emission computed tomography (SPECT) with ATP can predict the rate of hard events. We studied 299 patients (188 men; mean age, 64 +/- 10 years) with known or suspected coronary disease with thallium 201 SPECT during ATP infusion and at rest. Perfusion defects were divided into the following: absent/mild reversible, moderate/severe reversible, and mixed/fixed. During a maximum follow-up of 87 months (mean, 32.7 +/- 20.3 months), the rate of cardiovascular events was studied. The prognostic value of different variables that can influence survival was calculated with the Cox proportional hazards model. The total number of cardiovascular events was 115 (43 hard events). The annual rate of hard events according to type of perfusion defect was 3.44% (95% confidence interval [CI], 2.12-5.26) for absent/mild reversible, 6.06% (95% CI, 2.23-13.20) for moderate/severe reversible, and 15.12% (95% CI, 8.64-24.55) for mixed/fixed. In the Cox model the variables that significantly predicted hard events were age greater than 55 years (P = .0293), diabetes (P = .0036), and severe perfusion defects (P = .0008). ATP can be used for pharmacologic stress testing. SPECT with ATP has a stronger correlation with the rate of hard events than clinical variables.

Surveillance study for creating the national clinical database related to ECG-gated myocardial perfusion SPECT of ischemic heart disease: J-ACCESS study design

ECG-gated myocardial perfusion SPECT is widely applied to diagnose ischemic heart disease, and such findings are useful to predict patient prognosis. However, Japan does not have a database that correlates SPECT image findings with the prognosis of patients who have ischemic heart disease. A large-scale clinical study involving 117 medical facilities throughout Japan was established to survey the clinical background and image findings of patients who have undergone ECG-gated stress perfusion SPECT. These patients were followed up for three years to investigate the occurrence of cardiac events. The 4,629 registered patients comprised 2,989 males (age 64.9 +/- 10.3 y, mean +/- SD) and 1,640 females (age 67.2 +/- 9.7 y). The most frequent complication was hypertension (54.5%), followed by hyperlipidemia (47.2%) and diabetes (29.4%). Percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) was conducted on 1,925 of the patients. SPECT examinations were ordered for further examination of chest pain (32.8%), periodic follow-up after coronary artery intervention (24.2%), screening for coronary artery disease (15.1%), follow-up of old myocardial infarction (14.9%), more detailed investigation of ECG or echocardiographic abnormalities (13.1%), etiological assessment of heart failure (1.6%), and further inspection for acute coronary syndrome (0.3%). The method of inducing stress was most often exercise loading at 68.8%, and infusion of either dipyridamole (14.6%) or adenosine triphosphate (ATP, 13.8%). The most frequently applied amount of 99mTc-tetrofosmin was an initial dose of 200 to 300 MBq combined with a second dose of 700 to 800 MBq (37.7%). The mean doses were 305 +/- 81 at the initial and 709 +/- 132 MBq at the second administration. A history of angina pectoris (41.2%) was the most frequent, followed by myocardial infarction (29.5%). During the two years of follow-up after registration, 46 of the 4,629 subjects have discontinued or dropped out, 134 have died, and 4,449 (97.8%) continue to undergo follow-up investigations. A complete report will be presented when the follow-up data for 3 years have been compiled and analyzed.

Intracoronary Adenosine Triphosphate for Refractory Coronary Artery Spasm

A 62-year-old woman underwent aortic valve replacement for aortic stenosis. Her hemodynamics deteriorated with ST-T depression 6 hours postoperatively. Emergency coronary catheterization showed diffuse right coronary artery spasm. The spasm persisted despite intracoronary infusion of nitrates and calcium antagonists. Intracoronary adenosine triphosphate infusion finally resolved the spasm and stabilized the cardiac function.

Noninvasive Diagnosis of Restenosis by Transthoracic Doppler Echocardiography After Percutaneous Coronary Intervention: Comparison With Exercise Tl-SPECT

Noninvasive methods that have the ability to accurately detect restenosis have been desired in the selection of patients requiring further angiographic evaluation. The present study sought to evaluate the diagnostic potential of transthoracic Doppler echocardiography (TTDE), a noninvasive method for evaluating coronary flow velocity reserve (CFVR), in detecting restenosis after percutaneous coronary intervention (PCI). We studied 107 consecutive patients 6 months after undergoing successful PCI on the left anterior descending coronary artery (LAD) lesions for relief of angina pectoris. The flow velocity in the distal LAD was measured by TTDE both at rest and during intravenous infusion of adenosine triphosphate. CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocities. We defined a reversible perfusion defect in exercise Tl-201 single-photon emission computed tomography (SPECT) as restenosis. The CFVR measurements by TTDE were compared with the results of SPECT. Complete TTDE data were acquired for 105 of the 107 study patients. A contrast agent was used to obtain adequate Doppler signals in 29 patients. Of the 105 patients, there were 18 patients with abnormal perfusion (group A) and 87 patients with normal perfusion (group B) in the LAD territories on Tl-201 SPECT. CFVR was greater in group B than in group A (1.7 +/- 0.5 vs. 3.7 +/- 0.8, P < 0.0001, respectively). There were 17 patients with CFVR < 2 and 88 patients with CFVR > or = 2. CFVR < 2 predicted restenosis determined by Tl-201 SPECT, with a sensitivity of 94% and a specificity of 100%. Noninvasive measurement of CFVR by TTDE accurately reflects the physiological severity of coronary narrowing due to restenosis after PCI. This method has possibility of reducing the number of unnecessary coronary angiographies after PCI.

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

Effect of Reactive Hyperemia After Coronary Recanalization on Myocardial Tissue Reperfusion by Thrombolysis In Myocardial Infarction Flow Grade in Acute Myocardial Infarction

Thrombolysis In Myocardial Infarction (TIMI) flow grade is widely used to evaluate myocardial tissue reperfusion in acute myocardial infarction (AMI), but the current grading system is incomplete. Therefore, we clarified the regulation of epicardial coronary flow velocity with the progression of microvascular dysfunction in AMI. We studied 36 patients with first anterior AMI. After intervention, we assessed TIMI flow grade and measured average peak velocity (APV) at baseline and after infusion of adenosine triphosphate (48 microg; baseline and hyperemic APVs, respectively) with a Doppler guidewire. We performed myocardial contrast echocardiography after 2 weeks to assess microvascular integrity (good reflow vs no reflow) and left ventriculography at admission and discharge (24 +/- 2 days) to measure regional wall motion (SD/chord). Patients were classified into 3 groups based on TIMI flow grade and microvascular integrity: TIMI grade 3 flow/good reflow (n = 16), TIMI grade 3 flow/no reflow (n = 12), and TIMI grade 2 flow (n = 8). Baseline APV was comparable in the patients with TIMI grade 3 flow but hyperemic APV was higher in patients with TIMI grade 3 flow/good reflow than in those with TIMI grade 3 flow/no reflow (hyperemic APV 59.3 +/- 25.8 vs 32.8 +/- 8.9 cm/s, p <0.01). All patients with TIMI grade 2 flow showed no reflow and the lowest values of baseline and hyperemic APVs. Regional wall motion at discharge was higher in patients with TIMI grade 3 flow/good reflow than in those with TIMI grade 3 flow/no reflow and TIMI grade 2 flow (-1.44 +/- 0.70, -2.69 +/- 0.31, and -2.88 +/- 0.48 SD/chord, respectively, p <0.01). In conclusion, compensatory reactive hyperemia preserves epicardial coronary flow velocity even in patients with microvascular damage, and with the progression of damage, this compensatory hyperemia can no longer preserve epicardial coronary flow velocity, and baseline APV is decreased in TIMI grade 2 flow.

Coronary Flow Reserve by Contrast Enhanced Transesophageal Coronary Sinus Doppler Measurements Can Evaluate Diabetic Microvascular Dysfunction

This study was undertaken to investigate whether coronary flow reserve (CFR) using coronary sinus flow (CSF), which can be measured by transesophageal Doppler echocardiography (TEDE), especially when contrast enhanced, is useful in evaluating microvascular dysfunction in patients with diabetes mellitus (DM). CSF recordings using contrast enhanced TEDE were performed before and after adenosine triphosphate infusion (0.15 mg x kg(-1) x min(-1)) in 16 patients with type 2 DM and diabetic retinopathy and in 13 non-DM patients (control). Coronary angiography revealed normal epicardial coronary arteries. CFR was defined as the ratio of the antegrade flow velocity time integral in hyperemic conditions and basal levels. Clear envelopes of CSF were obtained in all DM patients using contrast-enhanced TEDE. CFR using CSF in the DM group was significantly decreased compared with the control group (1.4+/-0.4 vs 2.1+/-0.5, p<0.01), but there were no significant differences of age, ejection fraction, rate of hypertension and hypercholesterolemia between the 2 groups. Using 1.7 of CFR as the cut-off value, diabetic microvascular dysfunction could be detected with 82% sensitivity and 83% specificity. CFR calculated by CSF using contrast-enhanced TEDE may be useful for evaluating diabetic microvascular dysfunction.

Effects of metabolic and myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic neuropathy in type 2 diabetes mellitus: A prospective study in Japanese patients

Background: In diabetic patients, cardiac autonomic neuropathy is an important factor affecting prognosis. Whether this condition in diabetic patients is caused directly by neurovisceral metabolic disorder and/or indirectly by micro circulation remains to be clarified. Objective: The aim of this study was to determine whether cardiac sympathetic nerve dysfunction can be detected using adenosine triphosphate (ATP) testing, while also investigating the effects of metabolic and/or myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic nerve dysfunction in patients with type 2 diabetes mellitus (DM-2) in Japan. Methods: This prospective study was performed at the Division of Diabetology Department of Internal Medicine, Toho University, Ohashi Hospital, Tokyo, Japan. Patients aged ≥ 18 years with DM-2 with no abnormalities on electrocardiography (ECG) or echocardiography were enrolled. An ATP thallium (Tl)-201 myocardial scintigraphy test (ATP test) and iodine (I)-123 metaiodobenzylguanidine (MIBG) scintigraphy were performed. ATP was administered by continuous IV infusion over 6 minutes at 0.16 mg/kg · min. Five minutes after the ATP infusion was started, T1-201 111 MBq IV was administered. Single-photon emission computed tomography (SPECT) imaging was begun immediately after the end of ATP infusion and was completed 3 hours after stress to show washout from stress to rest. I-123 MIBG 111 MBq IV was administered. A planar image from the front side and a SPECT image (early phase) was obtained 15 to 30 minutes later. After 3 hours, a planar image from the front side and a SPECT image (late phase) were obtained to show washout from stress to rest. The mean TI washout rate (ATP-WR) and heart-to-mediastinum (H/M) ratio in the late-phase scintigraphic images and the washout rate of MIBG (MIBG-WR) in the left ventricle was determined. The correlations of these measurements with the mean values of glycosylated hemoglobin (HbA 1c) and fasting plasma glucose obtained from monthly measurements over the previous 6 and 24 months were determined. Results: A total of 25 patients were enrolled (13 men, 12 women; mean [SD] age, 59.86 [8.28] years). Significant negative correlations between both ATP-WR and MIBG-WR and HbA 1c were found ( r = -0.52 [ P = 0.02] and −0.47 [ P = 0.03], respectively). Although no correlation was found between ATP-WR values and the early phase H/M ratio, a significant positive correlation was observed between ATP-WR and H/M ratio ( r = 0.54; P = 0.02). Conclusions: In the present study in Japanese diabetic patients without subjective signs of coronary artery disease and without abnormalities on ECG or echocardiography, ATP-WR, an indicator of myocardial blood flow, was correlated with myocardial sympathetic nerve dysfunction and 24-month glycemic control. However, sympathetic nerve dysfunction was not correlated with 24-month glycemic control.

Potentiation of Uterine Effects of Prostaglandin F2α by Adenosine 5′-Triphosphate

To investigate the interaction of exogenous adenosine 5'-triphosphate (ATP), a P2 receptor agonist, with prostaglandin F(2alpha) (PGF(2alpha)) on pregnant women in labor as well as on isolated human pregnant uterus preparations. For an in vitro study, myometrial samples were obtained from 27 women undergoing elective cesarean delivery at term. Concentration-response relationships for ATP (10(-8) -3 x 10(-4) mol/L), PGF(2alpha) (10(-9) -10(-5) mol/L), and their combination were obtained by using routine pharmacological organ bath technique. An in vivo study was performed with 34 pregnant women with dysfunctional abnormalities of the active stage of labor who were randomly allocated into 2 study groups. The women in the control group (18 patients) received intravenous prostaglandin F(2alpha) at an initial rate of 7.5 mug/min, whereas the women in the ATP group (16 patients) received prostaglandin F(2alpha) concomitantly with ATP (0.45 nmol/min, intravenously). Adenosine 5'-triphosphate at concentrations of 10(-6) -3 x 10(-4) mol/L and PGF(2alpha) at concentrations of 10(-8) -10(-5) mol/L caused concentration-dependent contractions of isolated smooth muscle preparations of the human pregnant uterus. At concentrations of 10(-6) mol/L and below, ATP had no effects on mechanical activity of the isolated uterus, but at concentrations of 10(-7) mol/L and 10(-6) mol/L, it significantly potentiated the contractile responses of the uterus induced by PGF(2alpha) (P < .05, 2-way analysis of variance). Patients receiving intravenous infusion of ATP as a supplement to PGF(2alpha) treatment, compared with those without ATP, had a significantly shorter interval from the start of the treatment to full cervical dilatation (3.31 +/- 1.49 hours and 4.67 +/- 1.11 hours in ATP and control groups, respectively; P = .014, Wilcoxon Mann-Whitney test). The total dose of prostaglandin received was significantly lower in the ATP group than that of controls (1,489.8 +/- 699.9 mug and 3,394.2 +/- 1,951.9 mug, respectively; P = .003, Wilcoxon Mann-Whitney test). No side effects of ATP treatment were observed during or after infusion. Adenosine 5'-triphosphate potentiates effects of PGF(2alpha) on pregnant human uterus in vitro and in vivo and thus could be a useful supplemental drug to increase uterine contractility at labor.

Experimental hyperhomocysteinemia impairs coronary flow velocity reserve

Background Hyperhomocysteinemia has been identified as an independent risk factor for coronary artery disease. One mechanism is considered to be deteriorated endothelial function that is recovered by vitamin C. However, its direct action on coronary circulation has yet to be examined. This study was designed to test the hypothesis that experimental acute hyperhomocysteinemia would impair coronary flow velocity reserve (CFR) by increasing oxidative stress. Methods Eleven healthy male volunteers (aged 23.3±0.9 years) were enrolled. CFR induced by intravenous 5′-adenosine triphosphate infusion was measured by transthoracic-Doppler echocardiography. Measurements were taken before and 4 h after administration of a placebo, oral methionine (L-methionine 0.1 g/kg) or oral methionine plus vitamin C (2 g) on 3 separate days. Results The baseline average diastolic peak velocity (APV) was similar in all 3 groups. In the methionine group, plasma homocysteine increased (12.9±7.0 to 32.1±9.4 nmol/ml, p<0.0001), while APV under hyperemic conditions (APV-hyp) and CFR significantly decreased (87.2±11.4 cm/sec and 4.02±0.70 to 73.2±10.2 cm/sec and 3.35±0.52, p=0.0022 and 0.0030, respectively). Moreover, there was a significant inverse correlation between the plasma homocysteine and CFR ( r=-0.620, p=0.0021). However, upon simultaneous administration of vitamin C, APV-hyp and CVR did not decrease despite an elevation in plasma homocysteine. Conclusions Experimentally induced acute hyperhomocysteinemia significantly decreased CFR, and this decrease was significantly reversed by vitamin C administration. Oxidative stress is suggested to play a major role in the deleterious effects of homocysteine on the coronary microcirculation.

Effect of botulinum toxin on detrusor overactivity induced by intravesical adenosine triphosphate and capsaicin in a rat model

Objectives To assess the effects of intravesical injection of botulinum toxin type A (BTX) on a model of detrusor overactivity induced by intravesical infusions of adenosine triphosphate (ATP) and capsaicin. BTX has recently been used clinically to treat overactive bladder syndromes without a precise knowledge of the mechanism of action. Methods Twelve Sprague-Dawley rats underwent BTX injections. Six received 1.0 U and 6 received 0.5 U. BTX injections were done at bladder tube placement. Ten rats received saline injections as controls. After 48 hours of recovery, all 22 animals underwent awake, conscious cystometrography (CMG), performed using both saline and ATP (20 mM) intravesical infusion at 0.074 mL/min. In another 4 rats, capsaicin (100 μM) was infused intravesically before and after the BTX injections. The CMG parameters calculated included bladder contraction pressures and contraction frequencies (contractions per minute or Herz). Results Intravesical saline CMG produced a contraction frequency of 0.78 ± 0.10 Hz. Intravesical ATP doubled this voiding frequency to 1.45 ± 0.18 Hz ( P = 0.003). BTX treatment at 1.0 U reduced the frequency to 0.91 ± 0.13 Hz ( P = 0.02). BTX injection significantly decreased the bladder contraction pressure during saline and ATP CMG. However, 0.5 U BTX did not decrease ATP-induced overactivity; therefore, in the capsaicin experiments, 1.0 U BTX was used. Although BTX tended to reverse detrusor overactivity secondary to intravesical capsaicin, this difference was not statistically significant. Conclusions Intravesical infusion of either ATP or capsaicin can induce detrusor overactivity. BTX was more effective in blocking the effect of ATP than of capsaicin, although BTX injection did show a trend in reducing the contraction frequencies and amplitudes induced by capsaicin. The clinical utility of using BTX to treat overactive bladder syndromes and bladder hypersensory states, especially those that may be caused by an augmentation of the purinergic pathway, should be studied further.

Myocardial Perfusion Imaging Using Adenosine Triphosphate Stress Multi-Slice Spiral Computed Tomography Alternative to Stress Myocardial Perfusion Scintigraphy

The present study was designed to: (i) detect myocardial ischemia in contrast enhanced multi-slice spiral computed tomography (CE-MSCT) using adenosine triphosphate (ATP) pharmacological stress test; and (ii) evaluate the potential of ATP stress CE-MSCT in a clinical setting. Twelve patients underwent ATP stress CE-MSCT and stress thallium-201 myocardial perfusion scintigraphy (MPS) and 9 of the patients received conventional coronary angiography (CAG). Dual CE-MSCT scans were performed for stress and rest images, with and without intravenous infusion of ATP (0.16 mg.kg-1.min-1) at intervals of 20 min. Myocardial perfusion and coronary artery were visually evaluated using MSCT and compared the results obtained from MPS and CAG. Of 36 territories, stress images of CE-MSCT described 26 hypo-perfusion areas and MPS described 22 redistributions. The agreement between MSCT and MPS was 83% (30/36, p<0.05). In 141 coronary artery segments of 9 patients undergoing CAG, rest images of CE-MSCT, which had significantly higher assessability than stress images (89% vs 48%, p<0.05), described 76% (13/17) of culprit coronary stenoses. Although CT-angiography should be currently assessed using rest images, ATP stress CE-MSCT can describe both ATP-induced myocardial ischemia and coronary artery stenoses in patients with coronary artery disease.

Reduced coronary flow reserve in patients with congestive heart failure assessed by transthoracic Doppler echocardiography

Although coronary flow reserve (CFR) has been reported to be restricted in various conditions, there has been no report of CFR for patients with congestive heart failure (CHF). The purpose of this study was to assess coronary flow characteristics for patients with CHF. We studied 15 patients with CHF: 8 with dilated myocardiopathy and 7 with hypertensive heart disease. Phasic coronary flow velocities were obtained in the left anterior descending coronary artery at rest and during hyperemia (0.15 mg/kg/min adenosine triphosphate infusion intravenously) by transthoracic echocardiography before and after treatment of CHF. CFR was obtained from the ratio of hyperemic/baseline diastolic mean velocity. CFR was significantly restricted in the condition of CHF compared with that after improvement of CHF (1.5 +/- 0.2 vs 2.0 +/- 0.3, P < .01). Baseline diastolic mean velocity in the condition with CHF was significantly greater than that after improvement of CHF (41 +/- 13 cm/s vs 33 +/- 13 cm/s, P = .04), although maximal hyperemic diastolic mean velocity was not significantly different before and after improvement of CHF (63 +/- 20 cm/s vs 61 +/- 19 cm/s, P = .68). After improvement of CHF, heart rate, along with left ventricular end-diastolic volume and dimension, were significantly decreased, and deceleration time of transmitral early filling flow was increased compared with before treatment of CHF. Blood pressure and ejection fraction were not significantly different before and after treatment of CHF. Restriction of CFR is demonstrated during CHF because of the elevation of baseline resting flow velocity, which might be related to increase in left ventricular preload and heart rate.

Adenosine triphosphate stress myocardial contrast echocardiography detects coronary artery stenosis with greater sensitivity than wall-motion abnormality measurements

Although stress myocardial contrast echocardiography (MCE) can be used to detect coronary stenosis, its efficacy relative to other methods, such as detection of wall-motion abnormalities, remains unknown. Thus, the goal of this study was to compare the sensitivity of MCE versus wall-motion abnormality detection in the assessment of coronary artery stenosis. Nine dogs with severe but nonflow limiting stenosis in the circumflex coronary artery underwent evaluation with real-time MCE along the short-axis view during infusion of Optison. The equation of y = a (1 - e -betat ) + c, which fits the replenishment curve of MCE, was calculated in the midseptum (normal region) and in the lateral wall (ischemic region) before and during adenosine triphosphate infusion. Wall-motion abnormalities were also evaluated by visual assessment and by measurement of wall thickening. Area under the receiver operating characteristic curve in beta- and A x beta-value, and percent wall thickening, was 0.963, 0.963, and 0.889, respectively, indicating that the diagnostic accuracy for detecting the coronary artery stenosis by real-time MCE was higher than that by the wall-motion assessment. Real-time MCE has higher sensitivity in detecting coronary stenosis during adenosine triphosphate stress test when compared with wall-motion assessment.