High Doses Of Adenosine Research Articles

Supraventricular Tachycardia, Types and Immediate Management; Experience at a Tertiary Care Hospital of South Punjab

Objectives: The objective of this study was to determine efficacy of different optimal adenosine doses in children presenting with supraventricular tachycardia (SVT) at a tertiary care hospital. Methods: A descriptive case series design was undertaken at the Department of Cardiology at the Chaudhry Pervez Elahi Institute of Cardiology in Multan between June 2021 and June 2022. Both genders, age groups less than 14 years, and patients with SVT. The data collection procedure involved the use of a specialized proforma to record the findings of the study. Adenosine was quickly dispensed in escalating doses of 100, 200, and 300 μg/kg. The reaction was captured using a 12-lead ECG, and instances of pre-excitation were noted. The success of the therapy was assessed by identifying a sustained sinus rhythm for a period exceeding three minutes as a positive outcome. Results: A total of 71 participants were included in the study. Out of these, 55 (77.5%) were males. 33.8% presented with a predisposing factor. The most common predisposing factor was LRTI and diarrhea in 47 (66.2%) patients. As per our findings, out of 71 patients who were administered 100 ug per kg of adenosine for SVT, 27 (38.0%) while the remaining refractory 42 patients were administered 200 ug per kg of adenosine. Out of these 42, 26 (61.9%) reverted back to sinus rhythm i.e. 200 ug per kg dose of adenosine was effective in 61.9% cases of SVT. The remaining patients reverted back at 300 ug per kg dose of adenosine. Conclusion: A higher dose of 200 ug per kg was effective in 61.9% of cases. This indicates that a higher dose of adenosine is more effective in treating SVT in children. Additionally, the study found that LRTI and diarrhea were the most common predisposing factors for SVT in children. These findings can be useful in improving the management of SVT in children, especially when considering the optimal dose of adenosine for treatment. Keywords: Adenosine, Supraventricular tachycardia, Pediatric cardiology, Dose optimization, Predisposing factors Sinus rhythm

Advantages of Modified Stoppa Approach in Mangement of Acetabular Fractures

This study presents our experience of internal fixation of the acetabular fractures and pelvic fractures using a newly modified Stoppa approach, which provides closer visualization to the entire anterior column, quadrilateral surface and the pelvic brim portion of the posterior column, and permits stable internal fixation for the acetabular fracture patterns with main anterior displacement and the anterior and lateral parts of the pelvis. The present study was a prospective clinical study including 10 patients with acetabular fractures who were treated operatively using modified Stoppa approach . The classification of acetabular fractures described by Letournel and Judet. All operative data was recorded Patients were followed-up for 12 months after the operation. The maximum displacement of the bony fragment was measured in the unit of mm by using PACS, Marosis mview ver. 5.4 Our result shows the incidence of perioperative complication. Two patients developed DVT and two patients developed obturator nerve palsy. Our result shows the radiological outcomes of the included patients. The mean CT gap was 1.685 ±0.27mm. Eighty percent of the patients had anatomical Matta class. Our result shows the Merle D‟Aubigne-Postel score of the included patients. Eighty percent of the patients had excellent score. The incidence of MVO after PPCI may be lowered by the addition of manual TA (6,24). The results of the present study show that the additional intracoronary administration of a high dose of adenosine may further improve STR up to 70%. Future larger studies with clinical endpoints are warranted to confirm the benefit of intracoronary administration of a high dose of adenosine in addition to glycoprotein IIb/ IIIa antagonist administration and TA in the setting of PPCI or rescue PCI.

Adenosine Attenuates LPS-Induced Cardiac Dysfunction by Inhibition of Mitochondrial Function via the ER Pathway.

Sepsis is a life-threatening organ dysfunction syndrome with a high rate of mortality. It is caused by an abnormal immune response to infection, and the occurrence of sepsis-induced cardiomyopathy is the primary cause of death. The present study was designed to examine the effects of adenosine on lipopolysaccharide- (LPS-) induced cardiac anomalies and the underlying mechanisms involved. Adenosine (25, 50, and 100 mg/kg, i.g., 2 times/day) was administered for three days, followed by the induction of sepsis by intraperitoneal injection of LPS (10 mg/kg/2h). The effects of adenosine on inflammatory factors, LVEF, LVFS, and MAPK in septic rats (half male and half female) were observed. Subsequently, the effect of adenosine (10 μM) on the mitochondrial function of H9c2 cells stimulated with LPS (20 μg/mL, 24 h) was observed in the presence and absence of the estrogen receptor-specific antagonist ICI182,780. The results show that medium to high doses of adenosine can significantly promote cardiac function (LVEF and LVFS) and reduce the levels of inflammatory factors (TNF-α, IL-6, PCT, and cTnI) and p-JNK in septic rats, with a significant difference seen between male and female rats. The results of flow cytometry show that adenosine significantly inhibited increases in ROS levels, mitochondrial membrane potential, and the swelling degree of mitochondria in H9c2 cells stimulated with LPS, but this effect could be blocked by ICI182,780, indicating that adenosine attenuated LPS-induced cardiac dysfunction by inhibiting mitochondrial function via the ER pathway.

Differential effect of adenosine on rhabdomyosarcoma migration and proliferation.

IntroductionAdenosine and its receptors are involved deeply in the regulation of tumour biology. Purine nucleotides are released from stressed cells in states of hypoxia or radiochemotherapy-induced cell damage. Adenosine exerts its effect through the P1 family of selective receptors. The purpose of the study was to evaluate the exact role of extracellular role on biology of Rhabdomyosarcoma (RMS) cells.Material and methodsSeries of in vitro studies accompanied by immunohistochemical, RQ-PCR and shRNA methods have characterised adenosine receptor expression on Rhabdomyosarcoma cell lines, normal skeletal muscle and effect of adenosine on Rhabdomyosarcoma growth and migration.ResultsExtracellular adenosine (highest at 50 μM, p < 0.05) and AMP (highest at 300 μM, p < 0.05) markedly enhanced chemotaxis in the Boyden chamber assay The reaction is mostly governed by the A1 receptor, which is greatly overexpressed in Rhabdomyosarcoma as compared with normal skeletal muscle. Cell migration induced by adenosine and AMP is blocked by pertussis toxin, phospholipase C and MAP kinase inhibitor, which demonstrates the importance of these signalling pathways. High doses of adenosine have a detrimental effect on cellular proliferation, in a receptor-independent manner (≥ 500 μM; p < 0.05). The blockage of adenosine transporter by dipyridamole abolishes this effect, indicating involvement of an intrinsic pathway. Further increase of adenosine concentration, induced by deaminase inhibitors, augment the effect.ConclusionsOur results suggest that adenosine and AMP trigger cell migration by binding to P1 receptors and directing cancer cells to the sites of hypoxia or cellular damage. Specifically by A1 receptor which is overexpressed in RMS.

Abstract 13031: A Randomized Trial Comparing the Effects of Ticagrelor versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease

Introduction: Ticagrelor is a reversible P2Y12 receptor antagonist used in patients with acute coronary syndrome (ACS). In the PLATO trial, treatment with ticagrelor reduced mortality compared to clopidogrel, to which pleotropic mechanisms may have contributed. In this study, we compared the effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease on myocardial blood flow (MBF) at rest and during intermediate and high dose adenosine infusion. Methods: Patients (n=22) were randomized using a double-blind crossover design to ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 5 days between the treatments. MBF was measured using Rb-82 PET-CT at baseline and at intermediate (80 mcg/kg/min) and high dose adenosine (140 mcg/kg/min). Results: Global MBF was significantly greater with ticagrelor versus clopidogrel at intermediate dose adenosine (1.28±0.55 versus 1.13±0.47, p=0.002), and not different at baseline (0.65±0.19 versus 0.60±0.15, p=0.4254) nor at high dose adenosine (1.64±0.40 versus 1.61±0.19, p=0.5302). In abnormal segments with low MBF reserve (&lt;2.5), MBF was significantly greater with ticagrelor compared to clopidogrel at intermediate and high dose of adenosine (p&lt;0.0001), with no difference at baseline. For segments with high MBF reserve (≥2.5 and &lt; 3.5), segmental MBF was significantly greater with ticagrelor compared to clopidogrel at baseline (p&lt;0.001) and at intermediate adenosine dose (p&lt;0.0001). Conclusions: Global stress MBF was greater with ticagrelor compared to clopidogrel during intermediate dose adenosine infusion. Regional MBF in segments with reduced MBF reserve was greater with ticagrelor compared to clopidogrel during intermediate and high dose adenosine. This suggests that ticagrelor may potentiate adenosine-induced myocardial blood coronary flow increases in patients with stable CAD compared to clopidogrel; an effect that may explain the observed incremental mortality benefit observed with ticagrelor.

The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine.

The NLR pyrin domain containing 3 (NLRP3) inflammasome is a major component of the innate immune system, but its mechanism of activation by a wide range of molecules remains largely unknown. Widely used nano-sized inorganic metal oxides such as silica dioxide (nano-SiO2) and titanium dioxide (nano-TiO2) activate the NLRP3 inflammasome in macrophages similarly to silica or asbestos micro-sized particles. By investigating towards the molecular mechanisms of inflammasome activation in response to nanoparticles, we show here that active adenosine triphosphate (ATP) release and subsequent ATP, adenosine diphosphate (ADP) and adenosine receptor signalling are required for inflammasome activation. Nano-SiO2 or nano-TiO2 caused a significant increase in P2Y1, P2Y2, A2A and/or A2B receptor expression, whereas the P2X7 receptor was downregulated. Interestingly, IL-1β secretion in response to nanoparticles is increased by enhanced ATP and ADP hydrolysis, whereas it is decreased by adenosine degradation or selective A2A or A2B receptor inhibition. Downstream of these receptors, our results show that nanoparticles activate the NLRP3 inflammasome via activation of PLC-InsP3 and/or inhibition of adenylate cyclase (ADCY)-cAMP pathways. Finally, a high dose of adenosine triggers inflammasome activation and IL-1β secretion through adenosine cellular uptake by nucleotide transporters and by its subsequent transformation in ATP by adenosine kinase. In summary, we show for the first time that extracellular adenosine activates the NLRP3 inflammasome by two ways: by interacting with adenosine receptors at nanomolar/micromolar concentrations and through cellular uptake by equilibrative nucleoside transporters at millimolar concentrations. These findings provide new molecular insights on the mechanisms of NLRP3 inflammasome activation and new therapeutic strategies to control inflammation.

Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans.

To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence. Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP.

Comparison of low and high dose intracoronary adenosine and acetylcholine in women undergoing coronary reactivity testing: Results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE)

Women with signs and symptoms of myocardial ischemia who are referred for invasive coronary angiography often have no evidence of obstructive coronary artery disease (CAD) [1]. Forty-five to sixty percent of these patients have abnormal coronary vasomotion due to endothelial or non-endothelial dependent macro- or microvascular coronary dysfunction [1–3]. Abnormal coronary vasomotion is linked with adverse cardiovascular outcomes, suggesting that additional coronary reactivity testing (CRT), beyond standard angiography, is needed in clinical practice to appropriately risk stratify these patients [2–6]. CRT with intra-coronary adenosine and acetylcholine (ACh) is used to identify vascular dysfunction, yet ascending dosing of these agents is time-consuming. We aimed to determine if 1) coronary flow reserve (CFR) was different after low or high dose adenosine, and 2) change in coronary artery cross sectional area (CSA) and coronary blood flow (CBF) was different after low or high dose ACh. Eighty -six women with no obstructive CAD, who were enrolled in the WISE Coronary Vascular Dysfunction Study (WISE-CVD, www.clinicaltrials.gov Identifier {type:clinical-trial,attrs:{text:NCT00832702,term_id:NCT00832702}}NCT00832702), underwent CRT using a Doppler guide wire (Volcano ®FloWire 300cm) in a proximal left coronary. CFR was recorded in response to low dose (18μg) and high dose (36μg) intra-coronary adenosine. Change in CSA and CBF were determined after intra-coronary low dose ACh (10−6 mol/L infusion for total of 0.364μg) and high dose ACh (10−4 mol/L infusion for total of 36.4μg). The protocol was approved by the local institutional review board, and written informed consent was obtained from each participant. On average, the women included in this analysis were 54 (±12.2) years old; 36.7% had hypertension; 13.9% had dyslipidemia; 45.6% had a history of tobacco use; 70.9% were Caucasian; and 10% had diabetes. The average CFR after low dose adenosine was 2.6 ± 0.6, and the average CFR after high dose adenosine was 2.5 ± 0.6. The CFR obtained after low dose adenosine was not significantly different from the CFR obtained after high dose adenosine in the same subject (mean of paired difference 0.06 ± 0.3, p-value = 0.11). The changes in CBF and CSA after low and high dose ACh are shown in the Table. On average CBF increased 15% ± 32% with low dose ACh, but increased 92% ± 102% with high dose ACh. In the same subject the increase in CBF was 77% higher after high dose ACh compared with after low dose ACh (p-value < 0.0001). The CSA of the proximal left anterior descending artery (LAD) and the LAD 5 mm distal to the flow wire remained essentially the same after low dose ACh, but decreased slightly after high dose ACh. On average, in the same subject the change in CSA of the proximal LAD was 4% smaller after high dose ACh compared with after low dose ACh (p-value = 0.05). Table Comparison of cross-sectional area and coronary blood flow change with use of low vs. high dose acetylcholine. Our data indicate that escalating dosing of adenosine to detect non-endothelial dependent microvascular coronary dysfunction may not be needed. These findings are consistent with previous work that suggests that intracoronary doses of adenosine as low as 16 μg achieve maximal hyperemia [7]. For the purpose of our testing, we have used relatively lower doses of adenosine (18 μg and 36 μg) that test its non-endothelial dependent effects on the coronary circulation. At higher doses of adenosine, it becomes an epicardial coronary vasodilator, and would test hyperemic CBF due to both endothelial and non-endothelial dependent effects [8]. Our ACh dosing was selected based on the pioneering work by Ludmer et al. that demonstrated that patients with atherosclerosis and suspected endothelial dysfunction have paradoxical vasoconstriction in response to intra-coronary infusions of ACh at doses of 10−6 mol/L or less [9]. Other studies have demonstrated a very high incidence of abnormal coronary spasm in response to intracoronary ACh in patients with suspected endothelial dysfunction when using even higher doses of intracoronary ACh (100–200 μg) [1,10]. The results of our analysis also suggest that higher dose ACh (36.4μg [10−4 mol/L]) has greater diagnostic utility than lower dose ACh (0.364μg [10−6 mol/L]), as higher dose ACh resulted in a significantly greater increase in CBF compared with low dose ACh, and on average only high dose ACh demonstrated an inappropriate decrease in CSA in this group of women with suspected endothelial dysfunction. Among women with evidence of ischemia but no obstructive CAD, low and high dose adenosine produced similar augmentation in coronary flow velocity, but low and high dose ACh produced different results. For clinically indicated CRT, low dose adenosine but high dose ACh appear to be indicated.

Effect of adenosine on melanogenesis in b16 cells and zebrafish.

BackgroundAdenosine is a nucleoside, in which an adenine molecule is attached to a ribofuranose sugar moiety. It can be released into the microenvironment by metabolically active cells, and then fulfills a multitude of functions in regulation of cell proliferation, by activating four subtypes of G protein-coupled adenosine receptors.ObjectiveIn this study, we investigated the effect of adenosine on melanogenesis, using B16 melanoma cells.MethodsThe toxic effects of adenosine on B16 melanoma cells were assessed. To understand the mechanism of the effect of adenosine on melanogenesis in B16 cells, melanin content and tyrosinase activity were measured. Tyrosinase, tyrosinase-related protein-1, and dopachrome tautomerase were monitored by Western blotting. Finally, adenosine was applied to zebrafish embryos, and its in vivo effect on pigmentation investigated.ResultsAt a low concentration, adenosine increased melanin content and tyrosinase activity, while a high dose of adenosine resulted in inhibition of tyrosinase activity. Western blotting showed that adenosine increased tyrosinase protein levels slightly, while high-dose adenosine decreased the expression of tyrosinase. In zebrafish tests, adenosine slightly inhibited body pigmentation.ConclusionIn this study, we investigated the effect of adenosine on melanogenesis, using the well-established B16 melanoma cell and zebrafish models. The results suggest that adenosine may inhibit pigmentation, through negative regulation of tyrosinase.

A Pharmacologic Study of Some Nucleosides and Nucleotides

Abstract Adenosine, adenosine-5′-phosphoric acid (AMP), adenosine-5′-triphosphate (ATP), guanosine-5′-triphosphate (GTP), uridine, uridine-5′-triphosphate (UTP), and cytidine diphosphate-5′-choline (CDPCh) were studied in vitro and in vivo. The intraventricular injection of high doses of adenosine, ATP, and methacholine into rats elicited clonic-tonic convulsions or an akinetic state, or both. Perfusion of frog hearts in situ with equimolar concentrations of the “high-energy” compounds, with the exception of ATP, failed to exert any positive inotropic effects, ATP did not potentiate the inotropic actions of (—)-adrenaline or (—)-noradrenaline. The cholinergic-like properties of adenosine and ATP were partially antagonised by concomitant perfusion with methylene blue, ATP, but not adenosine, obliterated transitorily, the cardio-toxicity of pilocarpine. The inhibition of the isolated clam heart by AMP and ATP qualitatively resembled the effects of acetylcholine (Ach). Antagonism of the cardio-depressant properties of AMP and ATP by benzoquinonium and 5-hydroxytryptamine (5-HT) also supports previous evidence that the adenyl compounds act similarly to the cholinergic mediator, ATP produced marked contractions and a tonotropic effect on the oestrogenised, isolated, quiescent rat uterus; these effects were destroyed by low concentrations of (—)-adrenaline and papaverine. Adenosine, AMP, and CDPCh in equimolarities elicited no response from this test preparation.

Adenosine transporter antagonism in humans augments vasodilator responsiveness to adenosine, but not exercise, in both adenosine responders and non‐responders

' We previously demonstrated a bimodal distribution of forearm vasodilator responsiveness to adenosine (ADO) infusion in the brachial arteries of human subjects. We also demonstrated that ADO receptor antagonism blunted exercise hyperaemia during heavy rhythmic handgripping, but vasodilator responses to exogenous ADO were only blunted in ADO responders. In this study, we continued investigating the contribution of ADO to exercise hyperaemia and possible differences between responders and non-responders. We hypothesized that ADO transporter antagonism would increase vasodilatation in response to exogenous ADO in responders only, but not effect exercise-mediated vasodilation. To test this hypothesis, we compared forearm vascular conductance (FVC) during infusion of ADO to FVC during handgripping before and after infusion of dipyridamole (DIP) in 20 subjects. In ADO responders, change in FVC above baseline (ml min-1 (100 mmHg)-1) for low, medium and high doses of ADO, respectively, was 58 +/- 8, 121 +/- 22 and 184 +/- 38, and after DIP was 192 +/- 32, 238 +/- 50 and 310 +/- 79. For non-responders, these values were 23 +/- 2, 43 +/- 5 and 66 +/- 9, respectively, before DIP (P<0.01 versus responders). Contrary to our hypothesis, these values were increased by DIP in non-responders (P<0.001) and therefore not different from responders (P>0.20). We found that ADO transporter blockade had no effect on exercise hyperaemia in either subgroup. We conclude that there may be increased ADO transporter activity in non-responders resulting in reduced ADO-mediated vasodilatation. The failure of DIP to augment exercise hyperemia under these conditions suggests that ADO concentrations may not rise enough during rhythmic handgripping to have a major impact on these responses.

Adenosine-induced cardiac arrest and EEG changes in patients with thoracic aorta endovascular repair

We studied haemodynamic and metabolic variables, and cerebral function after cardiac arrest induced by high dose of adenosine in patients undergoing thoracic aorta endovascular repair. Arterial blood pressure, blood gas values and EEG were recorded continuously in 15 patients undergoing anaesthesia (isoflurane) for endovascular thoracic aorta repair. Cardiac arrest was induced by different doses of adenosine (Adrekar, Sanofi-Synthelabo, Berlin, Germany; 0.4-1.8 mg kg(-1) body weight). Serum concentrations of neurone-specific enolase (NSE) were determined before and after stent graft implantation. Neurological function was assessed before and after surgery. After adenosine, the heart beat stopped immediately for 18-58 s in close relation to the adenosine dose. EEG power was significantly reduced to -57%, but reached normal values within 5 min after cardiac arrest. In particular, the fast alpha- and beta-EEG-frequencies sensitively reflected patients' EEG activity during the procedure. No intraoperative increases in NSE concentrations, and no neurological dysfunctions after surgery, were observed. After adenosine-induced cardiac arrest, changes in haemodynamic variables and EEG power spectra reversed completely within 1 and 5 min, respectively, without persistent brain dysfunction after stent graft implantation.

Influences of Adenosine Transporter Antagonism on Vasodilator Responses to Adenosine and Exercise in Humans

We previously demonstrated a bimodal distribution of vasodilator responsiveness to adenosine (ADO) infusion in human subjects: one subgroup demonstrated robust vasodilator responses to ADO (ADO responders) and the other showed blunted responses (non-responders). Furthermore, ADO receptor antagonism blunted ADO vasodilator responses only in ADO responders and blunted exercise vasodilation only at high workloads in both groups. To test the hypothesis that ADO transporter antagonism would augment vasodilator responsiveness to ADO and exercise only in ADO responders, we compared forearm vasodilation to intra-arterial infusion of three doses of ADO to vasodilation during three workloads of forearm handgrip exercise before and after ADO transporter antagonism with dipyridamole (DYP) in 10 subjects. In ADO responders (n=5), the change in forearm vascular conductance above baseline (ml min−1 100mmHg−1) for the low, medium, and high doses of ADO, respectively, was 61 ± 15, 117 ± 35, 164 ± 47 before DYP and 160 ± 50, 171 ± 59, and 216 ± 87 after DYP. For non-responders (n=5), these values were 20 ± 2, 36 ± 6, 57 ± 14 before DYP (P < 0.05 vs. responders) and were 159 ± 40, 293 ± 53, and 377 ± 82 after DYP (P > 0.05 vs. responders). ADO transporter blockade had no effect on exercise hyperemia in either group (P > 0.05 for pre vs. post-DYP). We conclude that there may be increased ADO transporter activity in non-responders resulting in increased clearance of ADO from the interstitium and that, in both subgroups, ADO is not obligatory for exercise hyperemia.

Optimal Dosage and Method of Administration of Adenosine for Measuring the Coronary Flow Reserve and the Fractional Flow Reserve in Koreans

Background and Objectives:The achievement of maximal vasodilatation is mandatory for obtaining valid measurements of the coronary flow reserve (CFR) and the fractional flow reserve (FFR). Recent studies have indicated that an incremental dose or a high dose of adenosine is necessary to achieve maximal hyperemia. We performed this study to examine the response of the physiologic parameters to different doses and to different methods of administration of adenosine in Koreans. Subjects and Methods:CFR: The CFR was measured in 25 consecutive patients with angiographically normal coronary arteries by using a Doppler wire. Three different doses (9, 18 and 36 μg in the left coronary artery (LCA), and 6, 12 and 24 μg in the right coronary artery (RCA)) of adenosine were used. FFR: In a phase I study, 102 consecutive patients with 188 intermediate lesions (160 LCA and 28 RCA lesions) underwent FFR measurements with using a pressure wire. Three different bolus doses (20, 40 and 80 μg) were administered in an incremental fashion. In a phase II study, the hyperemic efficacy of 3 different doses of intracoronary (IC) infusion (180, 240 and 300 μg/min) and of 3 methods of administration (IC infusion, intravenous infusion and IC bolus) were compared. Results:CFR: The higher 2 dose of adenosine had a tendency to achieve a higher CFR than the lower 1st dose. But when we increased the adenosine to more than 20 μg (LCA 36 and RCA 24 μg), there was a tendency towards obtaining a lower CFR than that obtained after the 2 dose of adenosine (LCA: 2.78±0.71 vs. 2.66±0.60, p=0.055, RCA: 3.19 ±0.88 vs. 3.04±0.80, p=0.86). FFR: Phase I: The dose of adenosine that achieved maximal hyperemia was 51 ±16 μg in the LCA and 35±20 μg in the RCA. In 73 (46%) of the LCA lesions and 12 (42%) of the RCA lesions, a further reduction of the FFR occurred when a higher dose of adenosine was used (LCA>40 ug, RCA>20 μg). Phase II: The FFR obtained after an IC bolus injection (0.83±0.06) was significantly higher than obtained with an IV infusion (0.79±0.07) and an IC (0.78±0.09) infusion (p<0.01). However, no difference in the FFR was observed for the IC and IV infusions. Conclusion:This study suggests that more than 20 μg adenosine does not have an additive effect on measuring the CFR. Adenosine 40 μg for the LAD and 20 μg for the RCA seems to be optimal as a intracoronary bolus injection for measuring the FFR in most cases. However, for the patients with borderline FFR, a higher bolus adenosine dose or an adenosine continuous infusion may be necessary. (Korean Circulation J 2006;36:300-307)

Maternal Death Following Medical Treatment of Paroxysmal Supraventricular Tachycardia in Late Gestation

We present an unusual case of maternal death following medical treatment of paroxysmal supraventricular tachycardia (PSVT) in late gestation. A 30-year-old woman, gravida 1, para 0, came to the outpatient clinic of our obstetrics and gynecology department at 35 weeks of gestation. She had suffered from palpitation and shortness of breath that lasted 3 days. Electrocardiographic examination revealed PSVT. Although intravenous administration of verapamil (5 mg) and adenosine (36 mg) effectively prevented the relapse of PSVT, the patient lost consciousness 30 minutes after her last dose of adenosine with sudden-onset convulsions. Despite immediate administration of advanced cardiac life support, she showed no signs of improvement and died. PSVT in late gestation can be associated with maternal death even following conversion to sinus rhythm using medical treatment. Clinical use of adenosine for PSVT should alert the clinician to the potential risk of administering a high dose of adenosine to a pregnant woman, which can lead to maternal mortality in late gestation. Administration of a high dose of adenosine was, in our opinion, partially responsible for the maternal death and intrauterine fetal demise in this case.

Combined use of adenosine and amrinone inhibits reperfusion injury of rat liver

Although intraportal infusion of adenosine suppressed the oxidative stress caused by activated neutrophils and attenuated ischemia-reperfusion injury of canine liver, high doses of adenosine elicit systemic hypotension. The present work demonstrates that combined use of low doses of adenosine and amrinone, a phosphodiesterase inhibitor, strongly inhibited reperfusion injury of the liver without eliciting hypotension. After 45 min ischemia followed by 60 min reperfusion of rat liver, low doses of adenosine and amrinone were administrated intraportally, resulting in significantly increased hepatic levels of cGMP, cAMP, nitrite plus nitrate in plasma, and decreased alanine aminotransferase in plasma without changing hemodynamics. Thus, intraportal administration of low doses of adenosine and amrinone increased the cyclic nucleotides, thereby improved microcirculation and attenuated reperfusion injury of the liver.

Sleep-inducing effects of adenosine microinjections into the medial preoptic area are blocked by flumazenil

Microinjection of a wide range of sedative agents, including triazolam, pentobarbital, ethanol and adenosine, into the medial preoptic area has been shown to increase sleep, suggesting that it is an important (though not necessarily the only) anatomic site mediating hypnotic effects of these compounds. The mechanism by which adenosine increases sleep at this site is not clear, but one possibility is that this is related to its effects on the GABA A-benzodiazepine receptor complex. In order to assess this possibility, this paper describes the administration of adenosine, alone and in combination with the benzodiazepine receptor blocker flumazenil, into the MPA. It was found that 12.5 and 25 nM of adenosine significantly reduced sleep latency and increased total sleep time. The sleep-inducing effect was blocked by flumazenil. Flumazenil caused a modest increase in total sleep, and prevented the increase in total sleep induced by the higher dose of adenosine. These data suggest that at least one aspect of the hypnotic properties of adenosine is mediated by a direct or indirect action on the GABA A-benzodiazepine receptor complex.

Adenosine use during aortocoronary vein graft interventions reverses but does not prevent the slow-no reflow phenomenon.

Slow or no reflow (SNR) complicates 10-15% of cases of percutaneous intervention (PI) in saphenous vein bypass graft (SVG). To date there have been limited options for the prevention and treatment of this common and potentially serious complication. We evaluated the procedural outcome of 143 consecutive SVG interventions. We compared patients who received pre-intervention intra-graft adenosine boluses with those who did not. In addition we examined the efficacy of adenosine boluses to reverse slow-no reflow events. Angiograms were reviewed and flow graded (TIMI grade) by film readers blinded to the use of any intraprocedural drug or clinical history. Seventy patients received intragraft adenosine boluses before percutaneous intervention (APPI), 73 received no preintervention adenosine (NoAPPI). There were no significant angiographic differences between the two groups at baseline. A total of 20 patients experienced SNR. The incidence of SNR was similar in the two groups (APPI = 14.2% vs. NoAPPI = 13.6%, P = 0.9). SNR was treated with repeated, rapid boluses (24 microg each) of intra-graft adenosine. Reversal of SNR was observed in 10 of 11 patients (91%) who received high doses of adenosine (>/=5 boluses, mean 7.7 +/- 2.6) and in 3 of 9 (33%) of those who received low doses (<5 boluses, mean 1.5 +/- 1.2). Final TIMI flow was significantly better in the high dose than in the low dose group (final TIMI 2.7 +/- 0.6 vs. 2 +/- 0.8, P = 0.04). No significant untoward complications were observed during adenosine infusion. These findings suggest that SNR after PI in SVG is not prevented by pre-intervention adenosine, but it can be safely and effectively reversed by delivery of multiple, rapid and repeated boluses of 24 microg of intra-graft adenosine.

Spinal cord morphology after chronic intrathecal administration of adenosine in the rat.

The endogenous compound adenosine is known to have various modulatory effects both in the peripheral and central nervous system. Adenosine and its analogues induce antinociception in animal models when administrated systemically and intrathecally (IT), both in acute and chronic models of pain. Before a new drug is introduced for spinal pain treatment in humans, experimental studies of neurotoxicity must be undertaken. This study was performed in rats in order to reveal morphological or morphometric signs of spinal cord damage after chronic (two weeks) administration of adenosine. After insertion of IT catheters, the animals were injected twice a day during two weeks with adenosine (100 microg) or saline (controls). Potential spinal neurotoxicity was evaluated morphologically by light and electron microscopy supplemented by a morphometric analysis. There were no signs of histologic changes indicating neurotoxic effects by any of the methods of analysis. The morphological findings in the adenosine treated rats did not differ in any case from those of the saline treated animals. The results suggest that chronic IT administration of a high dose of adenosine is not associated with neurotoxicity in the rat spinal cord.

Adenosine and Pediatric Supraventricular Tachycardia in the Emergency Department: Multicenter Study and Review

Study objective: To determine the frequency of successful cardioversion and the adverse effects of adenosine treatment in pediatric emergency department patients with supraventricular tachycardia (SVT). Methods: This was a multicenter descriptive study with both prospective (convenience sample) and retrospective (chart review) patient entry. The setting was 7 urban pediatric EDs with a yearly census range of 22,000 to 70,000 visits. Pediatric patients 18 years of age and younger who received intravenous adenosine for presumed SVT were eligible. Results: Six investigators from 7 pediatric EDs entered 82 patients with 98 presumed SVT episodes (52 prospective and 46 retrospective) into the study. Twenty-five episodes occurred in children younger than 1 year of age. Eight patients had congenital heart disease, 59 had a history of SVT, 43 were taking cardiac medications (digoxin in 27), 13 had a history of asthma, and 25 presented in compensated cardiogenic shock. A total of 193 intravenous doses of adenosine were administered; doses were classified as low (<.1 mg/kg [n=18]), medium (.1 to <.2 mg/kg [n=116]), or high (≥.2 mg/kg [n=59]). The dose range was .03 to .5 mg/kg, and only 2 doses were higher than .3 mg/kg. A total of 95 patient-events were determined to be SVT, all but 5 of which were atrioventricular (AV) node–dependent; 3 events were ventricular tachycardia. The overall cardioversion success rate of adenosine was 72% (71/98), and that for AV node–dependent SVT was 79% (71/90). Cardioversion was successful for 4 patient-events at a low dose, 44 at a medium dose, and 23 at a high dose of adenosine. Adverse effects occurred in 22 patients, and no patient had bronchospasm or hemodynamically significant arrhythmia. Conclusion: Intravenous administration of adenosine led to successful cardioversion in 72% of pediatric ED patient-events that were presumed to be SVT. A dose range of .1 to .3 mg/kg was found to be most effective. Adenosine was not associated with significant adverse effects. [Pediatric Emergency Medicine Collaborative Research Committee, Losek JD, Endom E, Dietrich A, Stewart G, Zempsky W, Smith K: Adenosine and pediatric supraventricular tachycardia in the emergency department: Multicenter study and review. Ann Emerg Med February 1999;33:185-191.]