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ATP and adenosine: biochemistry and metabolism
Adenosine triphosphate (ATP) is an endogenously occurring nucleoside triphosphate, which is ubiquitous in all cell types and constitutes the natural precursor molecule of adenosine, (AD) a purine nucleoside formed by adenine and ribose. One ATP molecule consists of three phosphate groups, and is synthetized by several enzymes, namely ATP synthase, from adenosine diphosphate (ADP) or adenosine monophosphate (AMP). ATP is generated during cellular respiration by substrate level phosphorylation and oxidative phosphorylation.1 The actions of ATP are different in the intracellular and extracellular compartment. The main role of intracellular ATP is as a coenzyme in many fundamental cellular processes, such as cellular metabolism and energy production. The extracellular ATP however acts a molecular mediator between cells, after being released from endothelial cells, erythrocytes, activated platelets, muscle and nerve fibers, ischemic, inflammatory and apoptotic cells. Experiment data point towards an increased cellular formation of AD when either the local tissue metabolic demand increases or the regional blood flow and oxygen delivery decreases, especially in tissues which rely to a large extent to oxidative phosphorylation for energy production. AD and ATP exert their physiologic signaling effects via binding two purinergic receptor families in the cell membrane, named adenosine receptor or P1 receptor and ATP receptor or P2 receptor. P1 receptors are G protein-coupled receptors and are further classified into A1R, A2AR, A2BR, and A3R. With regard to P2 receptors two types have been identified: P2X, which are ion channels, and P2Y which are G protein coupled receptors. The half-life of extracellular ATP is extremely short as it is catabolized rapidly by ecto-nucleotide enzymes which rapidly dephosphorylate extracellular ATP to ADP, AMP and AD, the latter in turn being subsequently transported back to the cytoplasm.2 Another secondary source of AD production within cells is the intracellular degradation of S-adenosyl-homocysteine, which is derived from S-adenosylmethionine via transmethylation reactions.3
Electrophysiologic effects of ATP and adenosine
In the cardiac conduction system, ATP and AD exert distinct negative chronotropic and dromotropic effects, by suppressing the sinus nodal automaticity and prolonging the conduction interval through the atrioventricular node (AVN). Intravenous administration of AD in humans has been demonstrated to cause sinus bradycardia and sinus arrest.4 Adenosine can also cause sino-atrial exit block at high concentrations, as well as a relocation of the earliest site of atrial activation from the sinus nodal region to the crista terminalis area.5 Interestingly, the sinus node (SN) is not the only site of the cardiac conduction system which manifests decreased automaticity after AD administration. The His-bundle and the Purkinje fibers have been shown to be even more responsive to AD, exhibiting a similar degree of decrease in automaticity with considerably lower doses of AD. With regards to the negative dromotropic action of AD it has been shown to increase the A-H interval in a dose-dependent manner, while it has no effect in the H-V interval.6 More specifically, it has been found that a suppression of nodal (N) cells action potentials accounts for 83% of the prolongation of the A-H interval caused by AD.7 Notwithstanding the inhibitory effects of AD in action potential propagation in the sinoatrial and (AV) node, AD has no impact in signal transduction through the atrial cell tissue.7 At the cellular level, AD induces a hyperpolarization of the resting potential across the membrane, a decrease in the slope of phase 4 depolarization, and a reduction in the action potential duration. In clinical settings the above effects are typically transient, with an approximate duration of 30 seconds followed by heart rhythm recovery without any clinically significant side-effects.8 Finally, a negative inotropic effect in atrial myocytes has been described.9
Extending beyond the cardiac conduction system, there is also a well-described effect in the coronary arteries, where ATP and AD induce vasodilation. Additional physiologic effects of AD comprise inhibition of platelet adhesion, anti-catecholaminergic actions, inhibition of renin production and sodium retention in the kidneys.10
Pathophysiogic differences in the effects of ATP versus adenosine
hen comparing the cardiac effects of ATP versus AD, a clear difference relies in the fact that the actions of ATP are evidently associated with the vagal tone. Specifically, maneuvers which enhance the parasympathetic afferent stimuli to the heart, such as physostigmine administration and increased plasma calcium levels, trigger an augmented effect of ATP over AD in the cardiac conduction system in experimental animal models.10 On the other hand, interventions which eliminate the vagal stimulation to the heart, such as administration of atropine or surgical denervation, practically render the ATP effects similar to those of AD.11 Furthermore, when the parasympathetic action in the heart is eliminated, the effects of ATP are counteracted by xanthine derivatives like aminophylline, which is a nonselective competitive antagonist of AD receptors, and upregulated by dipyridamole, which acts as an AD reuptake inhibitor.12 These data suggest that without the effects of the parasympathetic system, the actions of ATP in the heart are identical to those of AD. Of interest, the effects of ATP in the heart vary depending on the anatomical site of administration. In the left coronary artery, the vagal component of ATP action prevails while AD administration has no effects to SN automaticity.13 On the other hand, when administered to the sinus nodal artery, the effects of ATP are purely dependent in its subsequent degradation to AD.14 Detailed experimentation with regards to the potential targets and inhibitors of ATP binding revealed that ATP elicits a vagal depressor reflex response in the heart by means of upregulating specific receptors in the left ventricle.15
Safety and side-effects
During exogenous administration, ATP and/or AD are in general very well tolerated, can cause however transient bradyarrhythmias, as sinus bradycardia, sinus arrest or atrioventricular block. Facial flushing, headache, chest discomfort, sweating, dizziness and hyperventilation with dyspnea are also relatively common symptoms, but typically last for less than one minute and rarely are of clinical concern.16 However, the above effects are often pronounced in elderly patients, and therefore caution should be taken. In a few cases, acute exacerbation of asthma or chronic obstructive pulmonary disease with bronchospasm lasting for more than 30 minutes has occurred after AD administration.17,18 Also, AD has minor proarrhythmic effects and may cause atrial and ventricular ectopy as well as bradycardia-dependent polymorphic ventricular tachycardia, especially in patients with long QT syndrome.19 Rarely, AD may induce atrial fibrillation due to a suppression of the atrial refractoriness.20,21 This is potentially dangerous in the co-existence of ventricular preexcitation due to an accessory pathway which could rapidly conduct the atrial signal to the ventricles leading to ventricular arrhythmias. Hypersensitivity to AD has also been reported. Concomitant use of carbamazepine, digoxin, verapamil or dipyridamole increase the pharmacologic effects of AD.
Pathophysiologic basis of the usefulness of adenosine and ATP in the diagnostic investigation of syncopal attacks
The aforementioned cardiac effects of ATP and AD largely account for their widespread and recognized value in the diagnostic workup of neurally mediated syncope (NMS) and syncope of unknown origin (SUO). Their usefulness is explained by considering the proposed pathophysiology of NMS. In specific, it is postulated that an initial drop of systemic arterial pressure elicits an activation of the sympathetic system, which is in turn ensued by a disproportionate increase of parasympathetic discharges with concomitant sympathetic withdrawal, mediated by specialized cardiopulmonary mechanosensitive and chemosensitive receptors in the left ventricle.22 This paradoxical reaction stimulates a profound vasodilation and bradycardia which manifest clinically as presyncope and/or syncope. Exogenous administered ATP mimics this mechanism by inducing initially a sympathetic activation through a direct triggering of cardiac excitatory afferent fibers, followed by activation of vagal sensory nerve terminals that are localized in the left ventricle, which ultimately trigger a cardiocardiac central vagal depressor reflex.23-25 Noteworthy, AD exerts direct negative chronotropic and domotropic actions, but in contrary to ATP has no vagal activity.12 Instead, causes a continued sympathetic withdrawal that in susceptible individuals results finally in vasovagal syncope.26
S It has been postulated therefore, that ATP and AD endogenous production may be related to the clinical presentation and their exogenous administration would unmask syncopal symptoms in patients with NMS and SUO. In support of with this concept, patients with positive tilt test had higher AD plasma concentration and a positive association between the increase in AD levels and the onset of syncope exists.27 Also, patients with unexplained syncope and positive tilt test exhibit an overexpression of the AD receptor A2AR.28,29 Indeed, in some patients the cardiac effects of exogenous ATP/AD administration are exaggerated and result in paroxysmal AV block with long pauses. Therefore, the induction of clinically evident paroxysmal AV block with long periods of ventricular asystole following the injection of ATP/ AD has been suggested as a surrogate of increased risk in patients with syncope not been attributed elsewhere.
DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation1983;68:1254-1263.
Perennes A, Fatemi M, Borel ML, Lebras Y, L’Her C, Blanc JJ. Epidemiology, clinical features, and follow-up of patients with syncope and a positive adenosine triphosphate test result. J Am Coll Cardiol2006;47:594-597.
Pelleg A, Belhassen B, Ilia R, Laniado S. Comparative electrophysiologic effects of adenosine triphosphate and adenosine in the canine heart: influence of atropine, propranolol, vagotomy, dipyridamole and aminophylline. Am J Cardiol1985;55:571-576.
DiMarco JP, Miles W, Akhtar M, Milstein S, Sharma AD, Platia E, McGovern B, Scheinman MM, Govier WC. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Assessment in placebo-controlled, multicenter trials. The Adenosine for PSVT Study Group. Ann Intern Med1990;113:104-110.
Xu J, Kussmaul W, Kurnik PB, Al-Ahdav M, Pelleg A. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors. Am J Physiol Regul Integr Comp Physiol2005;288:R651-655.
Carrega L, Saadjian AY, Mercier L, Zouher I, Berge-Lefranc JL, Gerolami V, Giaime P, Sbragia P, Paganelli F, Fenouillet E, Levy S, Guieu RP. Increased expression of adenosine A2A receptors in patients with spontaneous and head-up-tilt-induced syncope. Heart Rhythm2007;4:870-876.
Deharo JC, Mechulan A, Giorgi R, Franceschi F, Prevot S, Peyrouse E, Condo J, By Y, Ruf J, Brignole M, Guieu R. Adenosine plasma level and A2A adenosine receptor expression: correlation with laboratory tests in patients with neurally mediated syncope. Heart2012;98:855-859.
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