The Janus Face of Adenosine: Antiarrhythmic and Proarrhythmic Actions

Send Orders for Reprints to [email protected]

Current Pharmaceutical Design, 2015, 21, 965-976 965

1873-4286/15 $58.00+.00 © 2015 Bentham Science Publishers

The Janus Face of Adenosine: Antiarrhythmic and Proarrhythmic Actions

A. József Szentmiklósi1#*, Zoltán Galajda2#, Ágnes Cseppent�1#, Rudolf Gesztelyi3, Zsolt Susán2, Bence Hegyi4 and Péter P. Nánási4,5

1Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Hungary;

2Department of

Surgery, Institute of Vascular Surgery, Faculty of Medicine, University of Debrecen, Hungary; 3Department of Pharmacodynamics,

Faculty of Pharmacy, University of Debrecen, Hungary; 4Department of Physiology, Faculty of Medicine, University of Debrecen,

Hungary; 5Department of Dental Physiology and Pharmacology, Faculty of Dentistry, University of Debrecen, Hungary

Abstract: Adenosine is a ubiquitous, endogenous purine involved in a variety of physiological and pathophysiological regulatory mechanisms. Adenosine has been proposed as an endogenous antiarrhythmic substance to prevent hypoxia/ischemia-induced arrhyth-mias. Adenosine (and its precursor, ATP) has been used in the therapy of various cardiac arrhythmias over the past six decades. Its pri-mary indication is treatment of paroxysmal supraventricular tachycardia, but it can be effective in other forms of supraventricular and ventricular arrhythmias, like sinus node reentry based tachycardia, triggered atrial tachycardia, atrioventricular nodal reentry tachycardia, or ventricular tachycardia based on a cAMP-mediated triggered activity. The main advantage is the rapid onset and the short half life (1-10 sec). Adenosine exerts its antiarrhythmic actions by activation of A1 adenosine receptors located in the sinoatrial and atrioventricular nodes, as well as in activated ventricular myocardium. However, adenosine can also elicit A2A, A2B and A3 adenosine receptor-mediated global side reactions (flushing, dyspnea, chest discomfort), but it may display also proarrhythmic actions mediated by primarily A1 adenosine receptors (e.g. bradyarrhythmia or atrial fibrillation). To avoid the non-specific global adverse reactions, A1 adenosine recep-tor-selective full agonists (tecadenoson, selodenoson, trabodenoson) have been developed, which agents are currently under clinical trial. During long-term administration with orthosteric agonists, adenosine receptors can be internalized and desensitized. To avoid desensiti-zation, proarrhythmic actions, or global adverse reactions, partial A1 adenosine receptor agonists, like CVT-2759, were developed. In ad-dition, the pharmacologically “silent” site- and event specific adenosinergic drugs, such as adenosine regulating agents and allosteric modulators, might provide attractive opportunity to increase the effectiveness of beneficial actions of adenosine and avoid the adverse re-actions.

Keywords: Adenosinergic drugs, antiarrhythmic action, proarrhythmic effect, adenosine A1 receptor activators, partial A1 adenosine receptor agonists, adenosine regulators, allosteric receptor modulators, drug development.

INTRODUCTION

Cardiac arrhythmias are one of the major concerns in the cur-rent medical practice, since both atrial and ventricular arrhythmias carry significant morbidity and mortality. Over the last century, there has been an intensive effort to develop effective and specific antiarrhythmic agents. In spite of the enormous endeavour, the antiarrhythmic drugs available in the clinical practice – with some exceptions – have moderate potency for preventing and treating the various rhythm disturbances. In addition, these drugs have also the potential for serious adverse reactions. There is no doubt that intro-duction of new pharmacological strategies is inevitable.

It is known that during pathological conditions, primarily in myocardial ischemia, a number of arrhythmogenic substances (e.g. catecholamines, histamine, thromboxane, 5-hydroxytryptamine, potassium, etc.) are released in the heart [1]. Concomitantly, as a counteraction, various protective substances are also liberated. För-ster [2] was the first to describe that under hypoxic conditions a variety of prostaglandins (PGE1, PGE2, PGF2�) are produced in the heart and these substances have significant antiarrhythmic activity in experimental animals. He suggested that intensification of this endogenous protective function of prostaglandins can be a novel approach to therapy of various cardiovascular diseases, such as ventricular arrhytmias [1, 2]. In addition to prostaglandins, plasma kinins, which are also generated during myocardial ischemia, are capable of suppressing ventricular arrhythmias induced by ischemia *Address correspondence to this author at the Department of Pharmacology and Pharmacotherapy, University of Debrecen, P.O. Box 12, H-4012 Debre-cen, Nagyerdei krt. 98. Hungary; Tel: +36-52-427-899; Fax: +36-52-427-899; E-mail: [email protected] #These authors have contributed equally to this work.

[1, 3-5]. Nitric oxide can also be concerned as an endogenous myo-cardial protective and antiarrhythmic substance [1, 6, 7].

In this paper, we focus on adenosine, an endogenous metabolite playing a crucial role in physiological and pathophysiological func-tions of the pacemaker cells, specialized conductive tissues, work-ing myocardium and coronary arteries [8-15]. Adenosine is released in high quantity during myocardial hypoxia or ischemia and has a great impact as either a protective agent or a pathogenic factor un-der various conditions. There are experimental data suggesting that adenosine is an effective compound to suppress supraventricular and certain types of ventricular arrhythmias induced mainly by ischemia and catecholamine administration [1, 16-18]. Although adenosine is a prototypic drug for termination of paroxysmal su-praventricular tachycardia, there are promising human observations on the effectiveness of adenosine and adenosinergic drugs in treat-ment of several other forms of cardiac arrhythmias. Significance of the present and future adenosinergic therapy can be reflected by the fact that until recently a great deal of international clinical trials have been completed or under progress with these agents (e.g. AMISTAD I, AMISTAD II, ADVICE, ADELINE, PROTECT, TEMPEST, ADVANCE MPI1, ADVANCE MPI2, THE REOPEN-AMI STUDY, ADVISE II, RABIT1D) [19-21].

ADENOSINE RECEPTORS IN THE CARDIOVASCULAR

SYSTEM

Drury and Szent-Györgyi [22] as early as in 1929 observed that adenosine and other adenine compounds had profound actions in the cardiovascular system. Since that time a remarkable progress has been occurred with milestones like the elaboration of the adenosine theory of metabolic regulation of coronary circulation by Robert Berne and his coworkers [8, 9], or establishment of the con-

966 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

cept of purinergic receptors by Geoffrey Burnstock [23, 24] which was a cornerstone for adenosine receptor nomenclature. Burnstock was the first to propose the classification of receptors for adenosine and adenine nucleotides as the P1 and P2 purinergic receptors [24, 25]. P1 receptors are activated by adenosine, whereas P2 receptors can be stimulated by ATP and ADP. Four subtypes of adenosine receptors have been identified as A1, A2A, A2B and A3. Characteri-zation of these subtypes is based on their pharmacological profiles (i.e. rank order of potency of agonists and antagonists), G-protein coupling, and the signaling mechanism implicated in the subtype-specific adenosine receptor activation. This approach meets the criteria of the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification [26].

The role of A1 receptors is prominent in the antiarrhythmic therapy. A1 adenosine receptors are predominant in sinoatrial node, atrial working myocardium, atrioventricular node and presynapti-cally on adrenergic nerve varicosities in the heart. They are also expressed in the cerebral cortex, cerebellum, hippocampus, dorsal horn of spinal cord, eye, and adrenal gland, as well as in skeletal muscle, liver, and renal tissues. The cloned adenosine A1 receptor is a glycoprotein consisting of 326-328 amino acids and having a molecular weight of 36 kD [26-28]. The A1 receptor is coupled to a variety of intracellular second messengers through Gi/o and Gq/11 G proteins having inhibitory character [29, 30]. Stimulation of A1 receptors exerts an inhibition of adenylate cyclase activity leading to decrease of intracellular cyclic adenosine monophosphate (cAMP). A1 receptor stimulation can also result in activation of an inwardly rectifying potassium current (IK-Ado), modification of the activity of phospholipase C (PLC), protein kinase C (PKC), as well as sarcolemmal and mitochondrial ATP-sensitive potassium chan-nels [30-34]. The extent of inhibitory effect of A1 adenosine recep-tor stimulation on adenylate cyclase was shown to be strongly de-pendent on the initial magnitude of adenylate cyclase activity. Ac-cordingly, adenosine exerted a more pronounced inhibition on adenylate cyclase when this enzyme was activated by specific agents, like catecholamines [35]. Activation of inwardly rectifying potassium channels was significant only in the atrial myocardium since in ventricular myocardium the IK-Ado channels are practically absent. The effects of adenosine in the SA node, AV junction, Purk-inje fibers, and atrial working myocardium are largely based on the suppressive action of this purine nucleoside on adenylate cyclase activity and IK-Ado [36]. A1 receptor stimulation is capable of acti-vating nitric oxide synthase (NOS) enhancing thus nitric oxide (NO) content of the tissues. This way, NO can also be implicated in the inhibitory action of adenosine on the slow inward calcium cur-rent both in the SA [37] and AV nodal tissues [38].

A2A adenosine receptors are also widely distributed in various tissues. Density of A2A receptors is high in spleen, thymus, leuko-cytes, platelets, corpus striatum, nucleus accumbens, and olfactory bulb. Moderate expression can be found in the heart, lung and blood vessels. It consists of 410-412 amino acids and its molecular weight is around 45 kD [39, 40]. It is remarkable that A2A receptors could be desensitized more rapidly than the A1 subtype [41]. A2A recep-tors are associated with Gs proteins or with members of the Gq/G11 family activating adenylate cyclase or adenylate cyclase plus phos-pholipase C, respectively [30, 42, 43]. As for the antiarrhythmic activity of adenosine, it is interesting to note that A1 and A2A adenosine receptors can operate antagonistically in the heart [44].

A2B adenosine receptors are expressed primarily in the cecum, colon, and urinary bladder, while their density in the blood vessels, lungs, eyes, median eminence, and mast cells is moderate [26]. A2B adenosine receptor is considered as a low affinity receptor, and adenosine concentrations higher than 10 �M are needed to stimu-late this receptor subtype [45, 46]. A2B receptor is coupled to Gs proteins stimulating adenylate cyclase. These receptors are mainly

responsible for the adverse reactions during adenosine administra-tion in case of cardiac arrhythmias.

Tissue distribution of A3 adenosine receptors is strongly species dependent. A3 receptors are associated with adenylate cyclase via Gi2, 3. These receptors can also be coupled to Gq/11 proteins, result-ing in stimulation of phospholipase C with a consequent production of inositol 1, 4, 5-trisphosphate and Ca2+ liberation from the sarco-plasmic reticulum. In point of view of drug development, it is noteworthy that A3 receptors show an extreme inclination to desen-sitization following exposure to agonists (t1/2 ~10 min). The mecha-nism underlying this fast desensitization is phosphorylation by G-protein-coupled receptor kinases and the concomitant receptor in-ternalization [47].

ELECTROPHYSIOLOGICAL ACTIONS OF ADENOSINE ON SPECIALIZED PACEMAKER FIBERS AND THE CON-

DUCTIVE SYSTEM

Adenosine has a prominent activity on the cardiovascular sys-tem and is basically involved not only in the local control of blood flow, but also in regulation of cardiac pacemaker activity and atrioventricular conduction [9, 11, 15, 48-54]. One of the first rec-ognized actions of adenosine was the reduction of heart rate [22]. In sinoatrial nodal tissue, His bundle and Purkinje fibers of guinea pigs, adenosine exerts a suppressive effect on the spontaneous fir-ing rate of these pacemaker cells [55-62]. The Purkinje fiber has the highest sensitivity (EC50 = 3.5 �M), followed by the His bundle (EC50 = 10 �M), and the sinoatrial node (EC50 = 105 �M). These actions of adenosine are thought to be mediated by A1 adenosine receptors, which - when activated -enhance the inwardly rectifying potassium current (IK-Ado) resulting in hyperpolarization of the cell membrane and reduction of the slope of phase 4 depolarization [63-65]. In addition, adenosine is capable to inhibit the pacemaker cur-rent If in the SA and AV nodal cells [36, 66, 67]. West and Belardi-nelli [65] described that adenosine induced a pacemaker shift from the sinoatrial node to crista terminalis, and this pacemaker shift operated also in the His-Purkinje system [68]. Although, the exact mechanism of the extreme adenosine sensitivity of guinea pig Purk-inje fibers is still unidentified, it might probably be related to this pacemaker shift, or alternatively, with a higher density of adenosine receptors in this tissue. Honey and his colleagues observed as early as in 1930, as later by Di Marco et al. [56] that adenosine slowed the heart rate in humans. Watt and Routledge have shown in healthy volunteers that adenosine induced a transient, dose-dependent bradycardia with a subsequent sinus tachycardia [69, 70]. Endogenous adenosine production might have an implication in the hypoxia- or ischemia-induced bradycardia, since in spontane-ously beating guinea pig right atrial preparations the adenosine receptor antagonists aminophylline and 8-phenyltheophylline an-tagonized, whereas dipyridamole, a blocker of membrane purine transport, and the adenosine deaminase inhibitor coformycin en-hanced the hypoxia-induced suppression of the sinoatrial pace-maker activity [12, 71]. Watt proposed a fascinating theory, sug-gesting that adenosine might be involved in bradyarrhythmias re-lated to sick sinus syndrome in humans [72, 73]. Further clinical studies have shown that adenosine exerted significant suppressive action on human SA and AV nodal cells, however, adenosine failed to influence directly the automaticity in the human His-Purkinje system [74]. This action appears to be primarily antiadrenergic, since adenosine has only a slight effect on the firing rate of the His-Purkinje system in patients with complete atrioventricular blockade, but in the presence of isoproterenol the adenosine-induced suppres-sion of automaticity is accentuated. The antiadrenergic action of adenosine could be antagonized by aminophylline, a competitive antagonist of adenosine receptors [18]. The ability of adenosine to terminate ventricular tachycardia based on cAMP-mediated trig-gered activity can be explained by this antiadrenergic effect [75]. Adenosine is believed to mitigate the actions of catecholamines by a dual mechanism: adenosine activates the presynaptic A1 adeno-

Adenosine and Arrhythmia Current Pharmaceutical Design, 2015, Vol. 21, No. 8 967

sine receptors inducing an inhibition of norepinephrine release [76] and, in addition to this, it blocks postsynaptically the effects of catecholamines [18, 35, 77, 78].

Regarding the atrioventricular conduction, Drury and Szent-Györgyi recognized that adenosine and the other related compounds caused heart block [22]. Stafford observed that adenosine produced a concentration-dependent atrioventricular conduction block in guinea pig heart [79]. Later, the adenosine-induced impairment or blockade of atrioventricular nodal conduction was confirmed also in humans [80]. This block is usually a transient adverse reaction, but a prolonged and complete heart block, requiring temporary pacing, has also been reported [81]. Belardinelli et al. [36] reported that A1 adenosine receptors are highly expressed in the AV jun-ction. In addition, adenosine operates mainly on the proximal parts of the atrioventricular junction (atrio-nodal region and nodal re-gion), whereas the nodal-His bundle is insensitive to this nucleoside [82, 83]. According to Belardinelli et al. the adenosine-induced activation of inward rectifier potassium current, hyperpolarization of cell membranes, and suppression of the L-type calcium channels are equally involved in the slowing of AV conduction [36]. There are observations suggesting that endogenous adenosine can be in-volved also in the hypoxia-induced AV nodal conduction block [84].

ADENOSINE AS AN ANTIARRHYTHMIC AGENT

Over the past decades extensive evidence has been accumulated on the theory that adenosine is as a crucial endogenous antiar-rhythmic substance. Under various pathophysiological conditions a number of endogenous protective agents are released from the myocardium, e.g. prostaglandins [2], bradykinin [5], acetylcholine [85], nitric oxide, and also adenosine [1]. Among these molecules, recently a considerable interest has been focused on adenosine in both theoretical and clinical considerations, since it fulfills the basic criteria of an endogenous myocardial protective substance [16, 17]. One of these criteria is that exogenously applied adenosine should reduce the severity of life threatening ischemia-induced ventricular arrhythmias. Researchers from Parratt’s laboratory have first docu-mented that infusion of adenosine reduced the number of ventricu-lar ectopic beats, as well as the incidence and duration of ventricu-lar tachycardia in a rat coronary ligation model. In addition, high doses of adenosine fully prevented ventricular fibrillation [16]. In a dog model of coronary occlusion, the same group observed that continuous adenosine infusion was able to significantly reduce the incidence of severe post-occlusion arrhytmias, like multiple extra-systoles, ventricular tachycardia, and ventricular fibrillation [86]. Adenosine has primarily been shown to suppress ventricular ar-rhythmias when an increased catecholamine level was in the back-ground of disturbances. It was suggested that the antiarrhythmic action of adenosine can be due to the inhibition of norepinephrine release by activation of presynaptic A1 adenosine receptors in adrenergic varicosities [87]. On the other hand, it also can be sup-posed that adenosine mitigates the catecholamine-induced increase of cAMP, as well as the activation of ICa and transient inward cur-rent Iti [50]. The second expectation is that adenosine should be produced during myocardial ischemia in a sufficient amount to prevent these severe arrhytmias. Since the pioneering works of Berne’s laboratories [88-92], as well as Olsson and his coworkers [93, 94] there is no doubt that adenosine is released in increased amounts from the tissues under hypoxic or ischemic conditions. A number of experimental data on tissue concentration, interstitial level, and coronary blood adenosine concentrations are available under conditions of oxygen deprivation. According to these studies, it can be stated that adenosine concentrations can be high enough to exert antiarrhythmic activity [95-98]. The third criterion is that drugs which enhance or antagonize the actions of adenosine, should also appropriately enhance or antagonize, respectively, the severity of the ischemia-induced arrhythmias. The first approach of this point came from experiments with membrane purine transport in-

hibitors, which are capable of profoundly enhancing the adenosine concentration in the extracellular space. In a coronary occlusion model of pigs, it was observed that R75231, a highly potent inhibi-tor of membrane purine transport, effectively reduced the incidence of ventricular fibrillation [99]. Dipyridamole, a conventional mem-brane purine transport inhibitor was also able to prevent postocclu-sion ventricular arrhythmias in experimental animals [100].

It was shown in our earlier experiments that both aminophylline [71] and 8-phenyltheophylline [12] was able to prevent the hy-poxia-induced suppression of sinoatrial pacemaker activity in spon-taneously beating right atrial preparations of guinea pigs. Further-more, we have shown that inhibition of the enzyme adenosine deaminase by coformycin and the membrane purine transport by dipyridamole [71] significantly enhanced the hypoxia-induced bradycardia. Recently, these results were confirmed (Fig. 1) by the use of 2’-deoxycoformycin, a more specific inhibitor of adenosine deaminase, and S-6-(4-nitrobenzyl) mercaptopurine riboside (NBTI), a highly selective inhibitor of the nucleoside transporter. All of these agents significantly enhanced the adenosine content of myocardium under hypoxic conditions [101].

Its possible endogenous protective action makes adenosine to be an ideal therapeutic agent for treatment of various types of car-diac arrhythmias. This effect is based on profound actions on the electrophysiological properties of pacemaker cells, conductive tis-sues, working myocardium, as well as on its potent direct and indi-rect antiadrenergic effects.

Regarding potential clinical applications, excellent reviews are available in the literature presenting the past, present and future of adenosinergic agents [17, 19, 21, 50, 56, 74, 102-107]. The main clinical indications of adenosine are certain types of supraventricu-lar arrhytmias, especially tachycardias where the SA or AV node is involved in the reentrant circuit. Adenosine is particularly effective in paroxysmal supraventricular tachycardia (SVT) manifested mainly in pregnant women and children [108-112]. Somló, as well as and Komor and Garas were the first to describe the beneficial action of ATP (precursor of adenosine) on termination of paroxys-mal supraventricular tachycardia [102]. Later, Latour et al., as well as and Motté et al. studied the action of ATP in various types of tachycardias and found that ATP was highly effective in AV junc-tional tachycardia, while ineffective in ventricular tachycardia [102].

Over the past decades the actions of adenosine were extensively studied in various forms of supraventricular tachycardia. In tachy-cardia based on sinus node reentry, adenosine proved to be highly effective in human studies. A1 adenosine receptor stimulation in-duced the activation of outward potassium current with the conse-quent hyperpolarization. In sinus node, hyperpolarization resulted in sinus bradycardia or sinus arrest [64, 113, 114]. Engelstein et al. [114] reported that adenosine was ineffective in terminating the supraventricular tachycardia based on intra-atrial reentry and atrial flutter. In contrast, triggered atrial tachycardia was effec-tively suspended by adenosine [74, 114]. In this latter case, the mechanism of rhythm disturbance was delayed afterdepolarization, where the triggered activity is related to a catecholamine-induced increase of intracellular calcium. Since adenosine is known to de-crease the slow inward calcium current, the mechanism of termina-tion of tachycardia can well be explained. The results are variable in automatic atrial tachycardia [74, 103, 110, 114-116], since only transient termination and reduction of heart rate could be observed in most of the cases.

Adenosine was found to be highly effective in terminating su-praventricular tachycardia in cases when the AV node was involved in the reentrant circuit. AV nodal reentry tachycardia is the most common form of paroxysmal supraventricular tachycardia, in which adenosine easily terminates arrhythmia [56, 103, 109, 117]. In or-thodromic AV reciprocating tachycardia, the anterograde pathway

968 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

consists of atrial myocardium, AV node, and the His-Purkinje sys-tem, whereas the retrograde limb is an accessory pathway [50]. Interestingly, this accessory pathway is generally not sensitive to adenosine. Only those accessory pathways responded positively to adenosine where decremental conduction was involved in the reen-try [50]. In these cases the accessory pathway are partially depolar-ized so as the conduction is based on slow calcium current, that is why adenosine could block the reentry.

Regarding the usefulness of adenosine in ventricular tachycar-dia, it can be stated that most forms of ventricular tachycardias (bundle branch reentry, reentrant ventricular tachycardia, automatic tachycardia) are not sensitive to adenosine. This is true for ventricu-lar tachyarrhythmias based on coronary artery disease or diffuse cardiomyopathy [74]. In contrast, ventricular tachycardia based on a cAMP-mediated triggered activity is highly sensitive to adeno-sine. These tachycardias, developing usually in structurally normal heart after exercise or sympathetic overdrive, are due to delayed afterdepolarizations based on calcium overload [50].

The main therapeutical advantage of adenosine is that the onset of its action is very rapid (10-30 sec). It is metabolized in the blood by erythrocytes and endothelial cells. The half-life of adenosine ranges from 1 to 10 seconds [118-120]. It is applied as rapid bolus injections. Adenosine has a noticeable advantage over the classical drugs (verapamil, digoxin) applied in paroxysmal supraventricular tachycardia. Earlier verapamil was used as a standard therapy to terminate paroxysmal supraventricular tachycardia. In a retrospec-tive review study, Rankin and his associates compared the effec-tiveness of adenosine and verapamil against paroxysmal supraven-tricular tachycardia and have shown that while verapamil was suc-cessful in abolishing this arrhythmia in 81% of cases, adenosine was effective in 96% of the patients [121]. In contrast to adenosine, verapamil has a slower onset (1-2 min), a long duration of action, and a long-term hypotensive effect. Intravenous adenosine can in-duce, of course, adverse reactions, such as harmless burning, an-gina-like sensations in the chest and flushing. The adverse reactions are usually minor and self-terminated because of the rapid elimina-tion [122]. The side effects can primarily be attributed to activation of A2A adenosine receptors in various regions of the body. Auchampach and Bolli [44] raised an interesting hypothesis sug-gesting that A1 and A2A adenosine receptors operate antagonisti-

cally in the heart. This theory was based on the results of Norton et al. obtained in rat ventricular myocardium [123]. They proposed that both A1 and A2A adenosine receptors are expressed in ventricu-lar myocardium. A1 adenosine receptors mediate antiadrenergic actions, while A2A receptors serve to counteract the antiadrenergic effects of A1 receptors. In these studies, the antiadrenergic effect of adenosine was enhanced in the presence of specific A2A adenosine receptor antagonists. It was also proposed that selective modulation of adenosine receptors (stimulation of A1 with the concomitant inhibition of A2A receptors) might be more efficient in various car-diac arrhythmias. Therefore, combined treatment of A1 adenosine receptor agonists or adenosine enhancers with A2A receptor antago-nists may be useful to protect the heart from chronic sympathetic overdrive. In addition, it would be useful to apply specific A2A adenosine receptor antagonists simultaneously with adenosine to enhance the effectiveness of adenosine in terminating supraven-tricular tachycardia [44]. The principal advantage can be the at-tenuation of the A2A adenosine receptor-mediated unwanted actions (flushing, hypotension, etc.). Concomitant therapy of these selective adenosinergic drugs may open a novel therapeutic opportunity that can be operated in not only for adjustment of various types of car-diac arrhythmias, but also in other diseases, where one type of adenosine receptor (e.g. A2A) serves to counteract the perfect reali-zation of the A1 adenosine receptor-mediated actions.

Specific A1 adenosine receptor agonists were developed to achieve a more selective antiarrhythmic action with avoiding the A2A, A2B and A3 adenosine receptor-related adverse reactions. Until recently, two A1 adenosine receptor selective drugs were under clinical trial: selodenoson ((2S, 3S, 4R)-5-(6-(cyclopentylamino)-9H-purin-9-yl-N-ethyl-3, 4-dihydroxytetrahydrofuran-2-carboxa-mide) and tecadenoson (((2R, 3S, 4R)-2-hydroxymethyl)-5-(6-((R)-tetrahydrofuran-3-ylamino)-9H-purin-9-yl)-tetrashydrofuran-3, 4-diol)). Both compounds are derivatives of N6-cyclopentyl adenosine (CPA), a conventional experimental tool to study of A1 adenosine receptor-induced actions in various tissues [20, 124].

Tecadenoson (CVT-510) is a very specific full activator of A1 adenosine receptors (A1 adenosine receptor Ki = 3 nM). The actions of tecadenoson are more selective for A1 adenosine receptors in the atrioventricular node than in the sinoatrial node and atrial myocar-dium, therefore this drug causes bradycardia and atrial fibrillation

Fig. (1). Action of 2’-deoxycoformycin (� ; 10 �M; n = 5) and S-6-(4-nitrobenzyl) mercaptopurine riboside

� ; NBTI; 10 �M; n = 7) on the moderate hypoxia-induced decrease in sinoatrial pacemaker activity of spontaneously beating right atria of guinea pigs (n = 12). * P > 0.05; ** P > 0.01 ( � control) (Krebs solution, 37oC, gas phase: 5% CO2 + 95% O2 and 30% O2 + 5% CO2 + 65% N2 under normoxic and hypoxic conditions, respectively).

0 10 20 30 40 50 60 70 80 9020

40

60

80

100

120

***

**

**

** **** ** **

*

****

minutes during hypoxia

% o

f pre

-hyp

oxia

con

trol

Adenosine and Arrhythmia Current Pharmaceutical Design, 2015, Vol. 21, No. 8 969

less frequently [125, 126]. Its half life is approximately 30 min. In a proof-of-concept Phase III clinical study tecadenoson rapidly ter-minated the 86.5% of paroxysmal supraventricular tachycardias [127]. In the completed TEMPEST study (Trial to Evaluate the Management of Paroxysmal supraventricular tachycardia during Electrophysiological Study with Tecadenoson) the conversion rate was 50-90% depending on the dose applied. The main advantage of tecadenoson over adenosine is that tecadenoson is well tolerated and causes less atrial fibrillation, flushing, dyspnea and chest dis-comfort as adverse reactions [19, 21, 127, 128].

Selodenoson (DTI-0009) is also a highly selective A1 adenosine receptor full agonist (A1 adenosine receptor Ki = 6 nM). It has a longer half-life (150 min) than tecadenoson. In healthy volunteers, this compound seemed to be safe and well tolerated in clinical Phase I trial. The Phase II trial is conducted as a multi-center, ran-domized, double-blind, placebo-controlled study. This drug is indi-cated for treatment of chronic atrial fibrillation. Until now, since selodenoson showed only minimal side reactions, this drug can be considered as a promising tool in the future [21, 129, 130].

Trabodenoson (PJ-875, INO-8875) is a potent A1 adenosine receptor selective drug (A1 adenosine receptor Ki = 1 nM) with noticeable electrophysiological activity [131]. Mor et al. [131] ob-served an AV-node specificity with trabodenoson in rats. The com-pound is under Phase I/II clinical trial as an ophthalmic agent for assessing the reducing activity of intraocular pressure in glaucoma [132].

It is noteworthy that there are some further selective A1 adeno-sine receptor agonist (Fig. 2) aimed to use in the therapy of type 2 diabetes mellitus as insulin sensitizing agents (GR79236, CVT-3619). In addition, there are also trials with selective A1 adenosine activators to be used as anti-nociceptive (SDZ WAG 994) or antianginal drugs (capadenoson) [132, 133].

It must be noted that adenosine displays not only therapeutic actions, but it can also be used as an excellent diagnostic tool. Since adenosine fails to terminate all types of supraventricular tachycar-dias, primarily those which do not involve the AV node. In these cases, application of adenosine is able to unmask the pathological atrial electric activity. Several authors confirmed that the short-acting adenosine can be a useful tool in diagnosis of atrial flutter, atrial fibrillation and various arrhythmias based on multiple acces-sory pathways. The main diagnostic benefit of adenosine is to dis-tinguish between mechanisms underlying the narrow and wide complex tachycardias [102-104, 106, 107]. In addition, adenosine has been described to induce ectopic activity in electrically silent pulmonary veins ([134] and able to unmask the dormant pulmonary vein conduction after radiofrequency ablation ([135-138], therefore application of adenosine could be a useful diagnostic strategy and might help the effectiveness of pulmonary vein isolation.

PROARRHYTHMIC ACTIVITY OF ADENOSINE

Although, adenosine is a safe and effective antiarrhythmic agent, it was repeatedly observed that adenosine could induce vari-

Fig. (2). Chemical structures of adenosine and the main adenosine A1 receptor-selective agonists.

Adenosine CPA Tecadenoson

Selodenoson (DTI-0009) Trabodenoson (INO-8875) GR79236

CVT-3619 SDZ WAG 994 Capadenoson (BAY-68-4986)

O

OH OH

N

N

N

N

HN

HO

O

OH OH

N

N

N

N

NH2

HO

1

2

34

567

8 9

1'

2'3'

4'

5'O

OH OH

N

N

N

N

HN

HO

O

O

OH OH

N

N

N

N

HN

ON+

O-

O

O

OH OH

N

N

N

N

HN

HO

HO

O

OH OH

N

N

N

N

HN

S

OHF

O

OH O

N

N

N

N

HN

HO

CH3

NC N

NH2

S

CNO

OH

S

N Cl

O

OH OH

N

N

N

N

HN

HN OH3C

970 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

ous adverse reactions (flushing, dyspnea and chest discomfort) during intravenous injection, which effects were related to non-specific actions of this purine nucleoside on A2A, A2B and A3 adenosine receptors. More importantly, adenosine, like most other antiarrhythmic drugs, has also proarrhythmic effects. Adenosine, through activation of the A1 adenosine receptors, may induce tran-sient sinus arrest and bifascicular block [139, 140]. Sometimes, particularly after previous administration of verapamil or digoxin, complete heart block could also be observed [141]. Brodsky [141] and McCollam [142] reported asystole and ventricular standstill. In a study, Watt and Routledge [69] have shown transient bradycardia with subsequent sinus tachycardia followed by intravenous adeno-sine injection in 9 healthy adult subjects.

Adenosine induced atrial fibrillation in patients with paroxys-mal supraventricular tachycardia [117, 143, 144]. Strickberger et al. [144] observed atrial fibrillation in 11% of patients suffered with typical, 10% of atypical atrioventricular nodal reentrant tachycar-dia, and in patients with manifest (15%) and concealed (11%) ac-cessory pathways. The patients had no history of atrial fibrillation or atrial flutter [144, 145]. To explain the mechanism of this adeno-sine-induced atrial fibrillation, two theories have been elaborated. Accordingly, induction of atrial fibrillation needs a critical number of wavelets and a critical wavelength [146-148]. The wavelength depends on the refractory period and conduction velocity. The shorter the wavelength, the greater the probability of development of induction and maintenance of atrial fibrillation [147, 148]. Adenosine is thought to be shorten action potential duration result-ing in abbreviation of the refractory periods [49]. The second mechanism can be the development of frequent atrial premature complexes induced by adenosine. Consequently, the long-short atrial sequence might induce atrial fibrillation. One can suppose that the adenosine-induced increase in the circulating catecholamine level and the enhanced sympathetic outflow [149] promotes atrial premature complexes leading to develop long-short atrial sequences and atrial fibrillation [144].

Our previous findings confirms this hypothesis. In these ex-periments, adenosine shortened the effective refractory period in isolated, electrically driven guinea pig and cat atrial myocardium in a concentration-dependent manner, but had no effect on the refrac-tory period in electrically stimulated right papillary muscles of guinea pigs and cats. Aminophylline, a competitive antagonist on adenosine receptors, could significantly prevent the adenosine-induced shortening of the effective refractory period in atrial myo-cardium [150]. In anesthetized, open-chest cats atrial and ventricu-lar fibrillation threshold was determined during adenosine infusion (1 �mol/kg/min). It was found that the atrial fibrillation threshold gradually decreased by 21% during adenosine infusion and the susceptibility to fibrillation returned to the control value after cessa-tion of adenosine. In contrast, the fibrillation threshold of ventricu-lar myocardium failed to change by adenosine [150].

To analyze the role of A1 adenosine receptors in the reduction of atrial fibrillation threshold, further experiments were conducted in anesthetized, open-chest cats according to the original method of Szekeres and Papp [151]. In this arrangement the stimulating and recording electrodes were clipped to the right and left auricles. Electrical activity of the heart was continuously monitored by an oscilloscope, whereas the blood pressure in the common carotid artery was measured electromanometrically. For the induction of fibrillation, serial rectangular impulses were applied. The intensity of stimuli was increased until fibrillation or flutter developed. The occurrence of fibrillo-flutter was identified by direct observation of the heart, from the sudden drop in blood pressure, as well as from the ECG records. In these experiments, the atrial fibrillation thresh-old was determined under control conditions and also during infu-sion with 3 �mol/kg/min adenosine lasting for 8 min, and finally, during a 12 min period of washout. In another type of experiments, the animals were pretreated intravenously by 300 �g/kg DPCPX

(selective A1 adenosine receptor antagonist) and after a 8 min incu-bation time a 8 min infusion with 3 �mol/kg/min adenosine was commenced, which was followed by a 12 min washout period. Dur-ing adenosine infusion the atrial fibrillation threshold reduced by approximately 30% within 8 min after the onset of adenosine ad-ministration and returned to the control value upon washout. When the animals were pretreated by DPCPX, the decrease of atrial fibril-lation threshold significantly mitigated, indicating the role of A1 adenosine receptor activation in this process (Fig. 3).

As the role of catecholamines was concerned, experiments were performed also in anesthetized dogs by modification of the method of Maling and Moran [152] with continuous standard ECG record-ing. Arrhythmia was induced by intravenous administration of 100 �g/kg norepinephrine. The ventricular ectopic activity was the highest between 30 and 60 sec following the norepinephrine injec-tion. After then, the ectopic rate was progressively reduced (n = 5). In another type of experiments, 5 mg/kg adenosine was applied intravenously 1 min prior to administration of norepinephrine. The ventricular ectopic activity was not modified significantly by expo-sure to norepinephrine, but an atrial fibrillation was evident at 20-40 sec after norepinephrine injection in 80% of the animals. In ex-periments, where only adenosine were applied alone, no atrial fib-rillation was observed. These results call the attention for a specific interaction between norepinephrine and adenosine and demon-strates the catecholamine-dependence of adenosine-induced atrial fibrillation. It is likely that a synergistic interaction exists in the actions of adenosine and norepinephrine in shortening the duration of the atrial action potential and refractory period.

It has also been suggested that elevated levels of endogenous adenosine are implicated in a number of ischemia-related arrhyth-mias. Thus, myocardial ischemia can induce atrial fibrillation due to elevated adenosine concentration in the heart. Adenosine might have a pathophysiological role in development of post-transplantation bradyarrhythmia, too. Slow intravenous infusion of adenosine receptor antagonists (theophylline) was effective in these arrhythmias [153, 154]. Bertolet et al. [154] observed that intrave-nous bolus theophylline injection was able to effectively prevent the ischemia-induced atrioventricular block in patients with myocardial infarction. Watt [72, 73] was the first to suggest the hypothesis that adenosine can play a possible role in the pathogenesis of sick sinus syndrome. According to a randomized controlled trial (THEOPACE study) accomplished in patients suffering with symp-tomatic sick sinus syndrome, theophylline therapy was associated with a lower incidence of heart failure than those receiving no ther-apy [155]. These observations support the adenosine hypothesis of sick sinus syndrome.

CONCLUSION AND FUTURE DIRECTIONS

In the last decades there was an intensive effort to develop more and more effective antiarrhythmic agents having less and less side-effects. According to the clinical experience, however, the efficacy, safety and tolerability of these drugs did not always meet the requirements. For the treatment of certain types of arrhythmias, adenosine as an endogenous antiarrhythmic drug is a safe, effective and tolerable agent. The main advantage of the drug is the rapid onset and the fast elimination. Therefore, adenosine is close to the concept of the ideal drug. In spite of this, adenosine could also exert proarrhythmic activity.

The primary problem with adenosine is that this drug displays non-specific activity on A1, A2A, A2B and A3 receptors, conse-quently unwanted systemic adverse reactions (e.g. hypotension, chest discomfort, etc.) can be induced. To reach a selective A1 adenosine receptor-induced action, new, A1 adenosine receptor selective drugs were developed (tecadenoson, selodenoson, trabodenoson). These are full orthosteric agonists and have a num-ber of advantage over the non-selective adenosine, it should be taken into account that - because of the wide distribution of A1

Adenosine and Arrhythmia Current Pharmaceutical Design, 2015, Vol. 21, No. 8 971

adenosine receptors in the body - global adverse reactions can be anticipated with these agents in the cardiovascular or central nerv-ous system. Furthermore, during a long-term administration of adenosine receptor agonists, adenosine receptors can be internalized and desensitized, although the development of A1 adenosine recep-tor downregulation is not so rapid as in the case of A2A, A2B and A3 adenosine receptors [156].

In addition to the orthosteric full adenosine A1 agonists, there is a new trend in adenosinergic antiarrhythmic therapy, namely the introduction of partial adenosine A1 agonists (e.g. CVT-2759, ca-padenoson). Partial agonist is a drug that produces less than full effect, even if it has saturated the receptors. A partial agonist can operate as partially potent agonist or a weak antagonist depending on the tissue adenosine A1 receptor activity. These types of drugs may be a full agonist for one action, whereas may be partial agonist for another action in the same or different tissues depending on the receptor density or the signaling efficiency [126]. Srinivas et al. [157] observed that SHA-040, a partial adenosine A1 agonist, ex-erted 60% inhibition of the isoproterenol-stimulated calcium cur-rent, while it caused only a 20% activation of potassium current in guinea pig atrial myocytes. Wu et al. [126] demonstrated in guinea pig hearts that CVT-2759, a partial adenosine A1 receptor agonist, was able to cause a moderate and selective inhibition of AV con-duction, but failed to induce a second-degree AV block even when applied at high concentrations. This way, CVT-2759 may exert a moderate, predictable and submaximal inhibition of AV nodal con-duction, without the risk of serious AV block. These authors ob-served that CVT-2759 has only a very small action on the sinoatrial rate or on the duration of atrial and ventricular action potentials [126]. Therefore, CVT-2759 is not likely to induce atrial fibrillation or flutter. It is important to note that a partial A1 adenosine receptor agonist can induce less receptor downregulation and desensitization than a full agonist compound [158, 159]. Therefore, these drugs might be ideal for chronic treatment of certain cardiac arrhythmias. On the basis of these considerations, partial adenosine A1 receptor agonists can be promising antiarrhythmic agents without the global non-specific adverse reactions of adenosine. Recently, capadenoson (Fig. 2) as a partial adenosine A1 agonist is under Phase II clinical trial to investigate its effect on ventricular heart rate in patients with persistent or permanent atrial fibrillation [158]. It is important to see that during the application of orthosteric full agonists acting on adenosine receptors marked differences can be observed between their acute and chronic actions. Thus, long-term administration of adenosine receptor agonists may display

effects resembling the acute action of adenosine receptor antago-nists and vice versa [160]. Therefore, there are great efforts to de-velop such compounds that are pharmacologically “silent” and act only in the region of the actual problem, where adenosine level is elevated due to e.g. hypoxia, ischemia or inflammation. The aim is to prevent global adverse reactions and to confine the effects to those targets where pathological changes result in adenosine libera-tion. Such agents can be the site- and event-specific adenosinergic drugs. It is repeatedly noted that endogenous adenosine can play a significant role in terminating of cardiac arrhythmias and it is con-sidered as an important endogenous cardioprotective agent [161-163]. Therefore, the pharmacologically-induced enhancement of endogenous adenosine formation might be an attractive option to increase the effectiveness of beneficial actions of adenosine. The half-life of intravenously applied adenosine in the blood is very short (approx. 10 seconds). Within this short time, it is dubious that adenosine could reach all the cells potentially involved in its ar-rhythmogenic actions, since the vascular endothelium is a very effective metabolic barrier. Drugs, however, acting on the adeno-sine metabolism to enhance interstitial adenosine concentration can provide higher and more stable tissue adenosine levels in the af-fected region. Pharmacological possibilities for increasing the tissue adenosine concentration and effectiveness of adenosine receptor activation are as follows: (1) inhibition of membrane purine trans-port (dipyridamole, NBTI, draflazine, soluflazine), (2) inhibition of adenosine deaminase activity (coformycin, 2’-deoxycoformycin, EHNA, IADA-7), (3) inhibition of adenosine kinase enzyme (tu-bercidin, aristeromycin), (4) inhibition of AMP deaminase (GP3269), (5) activation of 5’-nucleotidase (methotrexate), (6) use of adenosine regulating agents (acadesine, GP 531) and (7) allos-teric adenosine modulation (PD81723, LUF6000 ) [164]. Prototypic compounds of these groups are displayed in (Fig. 4).

These are, of course, only theoretical possibilities except for the inhibitors of membrane purine transport. It is known that once pro-duced, extracellular adenosine is transported into the intracellular space by equilibrative and concentrative nucleoside transporters. Inhibitors of nucleoside transporters may have potential therapeutic benefits in treatment of various diseases. The conventional inhibitor of this membrane purine transport is dipyridamole (Fig. 4), which is capable of exerting antiarrhythmic activity similarly to adenosine [165]. Dipyridamole was described to have beneficial actions in treatment of reperfusion arrhythmias (accelerated idioventricular rhythms, triggered ventricular tachycardia) in patients with previous anterior wall myocardial infarction [165]. The advantage of dipyri-

Fig. (3). Effect of adenosine infusion (3 �mol/kg/min) on the fibrillation threshold of atrial myocardium of anesthetized, open-chest cats in the absence (� ; n = 7) and presence of 300 �g/kg DPCPX as a selective A1 adenosine receptor antagonist ( � ; n = 4). * P < 0.05.

0 4 8 12 16 20 24 2840

50

60

70

80

90

100

110

1203 �mol/kg/min adenosine

* *

min

Fibr

illatio

n th

resh

old

%

972 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

damole over adenosine is that dipyridamole has less suppressive action on sinoatrial automaticity and AV conduction. Disadvantage of the drug that it can induce coronary steal phenomenon [166], systemic hypotension [167] and has only poor oral bioavailability. An other inhibitor of membrane purine transport is lidoflazine, a drug being able to terminate atrial fibrillation in patients suffering with coronary heart disease [168]. Regarding drugs acting on adenosine deaminase, this enzyme also seems to be involved in initiating cardiac arrhythmias. Bernauer [169] observed that the incidence of reperfusion-induced ventricular fibrillation increased in hearts treated with adenosine deaminase. Therefore it is reason-able to assume that inhibitors of adenosine deaminase may display antiarrhythmic potency.

Because of the limitations of various site- and event specific adenosinergic drugs (inhibitors of membrane purine transport and adenosine deaminase), it appears that the most “silent” and effec-tive drugs might be the adenosine regulating agents and allosteric adenosine receptor modulators. Adenosine regulating agents have no cardiac or vascular actions under normoxic conditions, and more importantly, do not modify extracellular adenosine concentrations unspecifically, but effectively enhance the level of this purine nu-cleoside in the region exposed to ischemia [170]. Prototypic mem-ber of this group is acadesine, which has been suggested to exert significant cardioprotective effects in ischemia-reperfusion injuries [171].

Use of allosteric adenosine receptor modulators might be an original as well as a new approach in treatment of cardiac arrhyth-mias. It is known that adenosine receptors are allosterically regu-lated. Adenosine receptors contain an orthosteric binding site for binding of endogenous adenosine or selective adenosine analogues. Allosteric sites are different entities and their association with the modulator agent may induce conformational changes of the recep-

tor resulting in an enhancement of binding the orthosteric ligand [172]. Allosteric adenosine receptor enhancers stabilize the adeno-sine receptor-G protein complex and amplify the physiological action of adenosine. In the case of A1 adenosine receptors Asp55 in TM2 (second loop of transmembrane domain) was implicated in the allosteric regulation [172]. Until now, various potent allosteric adenosine receptor modulators have been developed, such are (2-amino-4, 5, 6, 7-tetrahydrobenzo[b]thiophen-3-yl)-(2-chloro-phenyl)-methanone (PD 71, 605), 2-amino-4, 5-dimethyl-3-thienyl-[3-(trifluoromethyl) phenyl] methanone (PD 81, 723), and (2-amino-6-benzyl-4, 5, 6, 7-tetrahydrothieno[2, 3-c]pyridin-3-yl)(4-chloro-phenyl) methanone (PD 117, 975). Among these, PD 81, 723 was shown to slow the A1 adenosine receptor-mediated atrioventricular nodal conduction, but did not influence the adenosine A2A receptor-mediated coronary vasodilation in guinea pig heart [173].

Allosteric adenosine receptor modulators might be useful agents to differentially modulate the efficacy of adenosine receptor activation of various regions of the heart in adenosine-sensitive cardiac arrhythmias. As for development and pharmacological ac-tions of these agents excellent previous works are referred [172-176].

Finally, it is worthy to consider that there is a growing body of evidence supporting the view that atrial fibrillation might be an inflammatory disorder [177]. This hypothesis was repeatedly con-firmed by elevation of inflammatory markers in serum or plasma, and morphological signs of inflammation in atrial biopsies from patients suffering from atrial fibrillation [178, 179]. In addition, there are promising results with a number of anti-inflammatory drugs, which can be, although variably, effective in prevention of atrial fibrillation. Since adenosine is generally thought to be an effective anti-inflammatory agent [180-182], a long-lasting modula-

Fig. (4). Prototypic members of site- and event specific adenosinergic drugs.

Dipyridamole

N

N

N

N

N

NNHO

OH

N

OH

OH

2’-deoxycoformycin Aristeromycin

GP 3269 Acadesine PD 81723

SH3C NH2

H3C O

CF3

O

OH

N

N

HON

NH

HO

OH OH

N

N

N

N

NH2

HO

O

OH OH

N N

N

HN

H3C

F

O

OH OH

N

N

NH2

NH2

O

HO

Adenosine and Arrhythmia Current Pharmaceutical Design, 2015, Vol. 21, No. 8 973

tion of certain cardiac adenosine receptor subtypes may offer a novel therapeutic approach for treating or preventing these widely distributed arrhythmias.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

This work was supported by TÁMOP-4.2.2.A-11/1/KONV-2012-0045. The project is implemented through the New Hungary Development Plan, cofinanced by the European Social Fund.

REFERENCES

[1] Parratt J. Endogenous myocardial protective (antiarrhythmic) substances. Cardiovasc Res 1993; 27: 693-702.

[2] Forster W. Prostaglandins and prostaglandin precursors as endogenous antiarrhythmic principles of the heart. Acta Biol Med Ger 1976; 35: 1101-12.

[3] Vegh A, Szekeres L, Parratt JR. Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetized dogs. Br J Pharmacol 1991; 104: 294-5.

[4] Martorana PA, Linz W, Scholkens BA. Does bradykinin play a role in the cardiac antiischemic effect of the ACE-inhibitors? Basic Res Cardiol 1991; 86: 293-6.

[5] D'Orleans-Juste P, de Nucci G, Vane JR. Kinins act on B1 or B2 receptors to release conjointly endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells. Br J Pharmacol 1989; 96: 920-6.

[6] Vegh A, Komori S, Szekeres L, Parratt JR. Antiarrhythmic effects of preconditioning in anaesthetised dogs and rats. Cardiovasc Res 1992; 26: 487-95.

[7] Rubanyi GM, Ho EH, Cantor EH, Lumma WC, Botelho LH. Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 1991; 181: 1392-7.

[8] Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 1963; 204: 317-22.

[9] Berne RM. The role of adenosine in the regulation of coronary blood flow. Circ Res 1980; 47: 807-13.

[10] Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 2007; 14: 1315-23.

[11] Szentmiklosi AJ, Nemeth M, Szegi J, Papp JG, Szekeres L. On the possible role of adenosine in the hypoxia-induced alterations of the electrical and mechanical activity of the atrial myocardium. Arch Int Pharmacodyn Ther 1979; 238: 283-95.

[12] Szentmiklosi AJ, Cseppento A, Gesztelyi R, et al. Xanthine derivatives in the heart: blessed or cursed? Curr Med Chem 2011; 18: 3695-706.

[13] Belardinelli L, Belloni FL, Rubio R, Berne RM. Atrioventricular conduction disturbances during hypoxia. Possible role of adenosine in rabbit and guinea pig heart. Circ Res 1980; 47: 684-91.

[14] Clemo HF, Bourassa A, Linden J, Belardinelli L. Antagonism of the effects of adenosine and hypoxia on atrioventricular conduction time by two novel alkylxanthines: correlation with binding to adenosine A1 receptors. J Pharmacol Exp Ther 1987; 242: 478-84.

[15] Szentmiklosi AJ, Nemeth M, Cseppento A, Szegi J, Papp JG, Szekeres L. Effects of hypoxia on the guinea-pig myocardium following inhibition of adenosine deaminase by coformycin. Arch Int Pharmacodyn Ther 1984; 269: 287-94.

[16] Boachie-Ansah G, Kane KA, Parratt JR. Is adenosine an endogenous myocardial protective (antiarrhythmic) substance under conditions of ischaemia? Cardiovasc Res 1993; 27: 77-83.

[17] Conti JB, Belardinelli L, Utterback DB, Curtis AB. Endogenous adenosine is an antiarrhythmic agent. Circulation 1995; 91: 1761-7.

[18] Lerman BB, Wesley RC, Jr., DiMarco JP, Haines DE, Belardinelli L. Antiadrenergic effects of adenosine on His-Purkinje automaticity. Evidence for accentuated antagonism. J Clin Invest 1988; 82: 2127-35.

[19] Ellenbogen KA, O'Neill G, Prystowsky EN, et al. Trial to evaluate the management of paroxysmal supraventricular tachycardia during

an electrophysiology study with tecadenoson. Circulation 2005; 111: 3202-8.

[20] Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 2006; 5: 247-64.

[21] Rizzolio F, La Montagna R, Tuccinardi T, Russo G, Caputi M, Giordano A. Adenosine receptor ligands in clinical trials. Curr Top Med Chem 2010; 10: 1036-45.

[22] Drury AN, Szent-Gyorgyi A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 1929; 68: 213-37.

[23] Burnstock G. Purinergic receptors. J Theor Biol 1976; 62: 491-503. [24] Burnstock G. Purinergic receptors in the heart. Circ Res 1980; 46:

I175-82. [25] Burnstock G. Purinergic nerves and receptors. Prog Biochem

Pharmacol 1980; 16: 141-54. [26] Fredholm BB, AP IJ, Jacobson KA, Linden J, Muller CE.

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. Pharmacol Rev 2011; 63: 1-34.

[27] Stiles GL. Adenosine receptors. J Biol Chem 1992; 267: 6451-4. [28] Shryock JC, Belardinelli L. Adenosine and adenosine receptors in

the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol 1997; 79: 2-10.

[29] Klotz KN. Adenosine receptors and their ligands. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 382-91.

[30] Headrick JP, Ashton KJ, Rose'meyer RB, Peart JN. Cardiovascular adenosine receptors: expression, actions and interactions. Pharmacol Ther 2013; 140: 92-111.

[31] Klinger M, Freissmuth M, Nanoff C. Adenosine receptors: G protein-mediated signalling and the role of accessory proteins. Cell Signal 2002; 14: 99-108.

[32] Lee JE, Bokoch G, Liang BT. A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. FASEB J 2001; 15: 1886-94.

[33] Henry P, Demolombe S, Puceat M, Escande D. Adenosine A1 stimulation activates delta-protein kinase C in rat ventricular myocytes. Circ Res 1996; 78: 161-5.

[34] Hu K, Duan D, Li GR, Nattel S. Protein kinase C activates ATP-sensitive K+ current in human and rabbit ventricular myocytes. Circ Res 1996; 78: 492-8.

[35] Bohm M, Bruckner R, Hackbarth I, et al. Adenosine inhibition of catecholamine-induced increase in force of contraction in guinea-pig atrial and ventricular heart preparations. Evidence against a cyclic AMP- and cyclic GMP-dependent effect. J Pharmacol Exp Ther 1984; 230: 483-92.

[36] Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995; 9: 359-65.

[37] Shimoni Y, Han X, Severson D, Giles WR. Mediation by nitric oxide of the indirect effects of adenosine on calcium current in rabbit heart pacemaker cells. Br J Pharmacol 1996; 119: 1463-9.

[38] Martynyuk AE, Kane KA, Cobbe SM, Rankin AC. Nitric oxide mediates the anti-adrenergic effect of adenosine on calcium current in isolated rabbit atrioventricular nodal cells. Pflugers Arch 1996; 431: 452-7.

[39] Olah ME, Stiles GL. Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol 1995; 35: 581-606.

[40] Olah ME, Ren H, Stiles GL. Adenosine receptors: protein and gene structure. Arch Int Pharmacodyn Ther 1995; 329: 135-50.

[41] Palmer TM, Gettys TW, Jacobson KA, Stiles GL. Desensitization of the canine A2a adenosine receptor: delineation of multiple processes. Mol Pharmacol 1994; 45: 1082-94.

[42] Kull B, Svenningsson P, Fredholm BB. Adenosine A(2A) receptors are colocalized with and activate g(olf) in rat striatum. Mol Pharmacol 2000; 58: 771-7.

[43] Fredholm BB, Arslan G, Halldner L, Kull B, Schulte G, Wasserman W. Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 364-74.

[44] Auchampach JA, Bolli R. Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges. Am J Physiol 1999; 276: H1113-6.

[45] Daly JW, Butts-Lamb P, Padgett W. Subclasses of adenosine receptors in the central nervous system: interaction with caffeine and related methylxanthines. Cell Mol Neurobiol 1983; 3: 69-80.

974 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

[46] Bruns RF, Lu GH, Pugsley TA. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol 1986; 29: 331-46.

[47] Trincavelli ML, Tuscano D, Marroni M, et al. A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation. Mol Pharmacol 2002; 62: 1373-84.

[48] Belardinelli L, Linden J, Berne RM. The cardiac effects of adenosine. Prog Cardiovasc Dis 1989; 32: 73-97.

[49] Belardinelli L, Lerman BB. Adenosine: cardiac electrophysiology. Pacing Clin Electrophysiol 1991; 14: 1672-80.

[50] Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine. Basic and clinical concepts. Circulation 1991; 83: 1499-509.

[51] Vinten-Johansen J, Thourani VH, et al. Broad-spectrum cardioprotection with adenosine. Ann Thorac Surg 1999; 68: 1942-8.

[52] Olsson RA, Pearson JD. Cardiovascular purinoceptors. Physiol Rev 1990; 70: 761-845.

[53] Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50: 413-92.

[54] Burnstock G, Ralevic V. Purinergic signaling and blood vessels in health and disease. Pharmacol Rev 2014; 66: 102-92.

[55] Versprille A. The chronotropic effect of adenine- and hypoxanthine derivatives on isolated rat hearts before and after removing the sino-auricular node. Pflugers Arch Gesamte Physiol Menschen Tiere 1966; 291: 261-7.

[56] DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L. Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 1983; 68: 1254-63.

[57] Szentmiklosi AJ, Nemeth M, Szegi J, Papp JG, Szekeres L. Effect of adenosine on sinoatrial and ventricular automaticity of the guinea pig. Naunyn Schmiedebergs Arch Pharmacol 1980; 311: 147-9.

[58] James TN. The chronotropic action of ATP and related compounds studied by direct perfusion of the sinus node. J Pharmacol Exp Ther 1965; 149: 233-47.

[59] Chiba S, Hashimoto K. Differences in chronotropic and dromotropic responses of the SA and AV nodes to adenosine and acetylcholine. Jpn J Pharmacol 1972; 22: 273-4.

[60] Urthaler F, James TN. Effects of adenosine and ATP on AV conduction and on AV junctional rhythm. J Lab Clin Med 1972; 79: 96-105.

[61] Pelleg A, Hurt C, Miyagawa A, Michelson EL, Dreifus LS. Differential sensitivity of cardiac pacemakers to exogenous adenosine in vivo. Am J Physiol 1990; 258: H1815-22.

[62] Pelleg A, Hurt CM, Michelson EL. Cardiac effects of adenosine and ATP. Ann N Y Acad Sci 1990; 603: 19-30.

[63] Belardinelli L, Isenberg G. Isolated atrial myocytes: adenosine and acetylcholine increase potassium conductance. Am J Physiol 1983; 244: H734-7.

[64] West GA, Belardinelli L. Correlation of sinus slowing and hyperpolarization caused by adenosine in sinus node. Pflugers Arch 1985; 403: 75-81.

[65] West GA, Belardinelli L. Sinus slowing and pacemaker shift caused by adenosine in rabbit SA node. Pflugers Arch 1985; 403: 66-74.

[66] Wang D, Belardinelli L. Mechanism of the negative inotropic effect of adenosine in guinea pig atrial myocytes. Am J Physiol 1994; 267: H2420-9.

[67] Pelleg A, Belardinelli L. Cardiac electrophysiology and pharmacology of adenosine: basic and clinical aspects. Cardiovasc Res 1993; 27: 54-61.

[68] Pelleg A, Mitamura H, Mitsuoka T, Michelson EL, Dreifus LS. Effects of adenosine and adenosine 5'-triphosphate on ventricular escape rhythm in the canine heart. J Am Coll Cardiol 1986; 8: 1145-51.

[69] Watt AH, Routledge PA. Transient bradycardia and subsequent sinus tachycardia produced by intravenous adenosine in healthy adult subjects. Br J Clin Pharmacol 1986; 21: 533-6.

[70] Watt AH, Bayer A, Routledge PA, Swift CG. Adenosine-induced respiratory and heart rate changes in young and elderly adults. Br J Clin Pharmacol 1989; 27: 265-7.

[71] Szentmiklosi J, Cseppento A, Szegi J. [Effect of adenosine on the electrical activity of the heart in experimental animals]. Acta Pharm Hung 1980; 50: 32-8.

[72] Watt AH. Sick sinus syndrome and adenosine. Lancet 1985; 1: 1340.

[73] Watt AH. Sick sinus syndrome: an adenosine-mediated disease. Lancet 1985; 1: 786-8.

[74] Wilbur SL, Marchlinski FE. Adenosine as an antiarrhythmic agent. Am J Cardiol 1997; 79: 30-7.

[75] Lerman BB, Belardinelli L, West GA, Berne RM, DiMarco JP. Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity. Circulation 1986; 74: 270-80.

[76] Lokhandwala MF. Inhibition of cardiac sympathetic neurotransmission by adenosine. Eur J Pharmacol 1979; 60: 353-7.

[77] Bohm M, Bruckner R, Meyer W, et al. Evidence for adenosine receptor-mediated isoprenaline-antagonistic effects of the adenosine analogs PIA and NECA on force of contraction in guinea-pig atrial and ventricular cardiac preparations. Naunyn Schmiedebergs Arch Pharmacol 1985; 331: 131-9.

[78] Belardinelli L, Vogel S, Linden J, Berne RM. Antiadrenergic action of adenosine on ventricular myocardium in embryonic chick hearts. J Mol Cell Cardiol 1982; 14: 291-4.

[79] Stafford A. Potentiation of adenosine and the adenine nucleotides by dipyridamole. Br J Pharmacol Chemother 1966; 28: 218-27.

[80] Toft J, Mortensen J, Hesse B. Risk of atrioventricular block during adenosine pharmacologic stress testing in heart transplant recipients. Am J Cardiol 1998; 82: 696-7, A9.

[81] Harvey MG, Safih S, Wallace M. Adenosine-induced complete heart block: not so transient. Emerg Med Australas 2007; 19: 559-62.

[82] Clemo HF, Belardinelli L. Effect of adenosine on atrioventricular conduction. II: Modulation of atrioventricular node transmission by adenosine in hypoxic isolated guinea pig hearts. Circ Res 1986; 59: 437-46.

[83] Clemo HF, Belardinelli L. Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node. Circ Res 1986; 59: 427-36.

[84] Xu J, Tong H, Wang L, Hurt CM, Pelleg A. Endogenous adenosine, A1 adenosine receptor, and pertussis toxin sensitive guanine nucleotide binding protein mediate hypoxia induced AV nodal conduction block in guinea pig heart in vivo. Cardiovasc Res 1993; 27: 134-40.

[85] Kent KM, Smith ER, Redwood DR, Epstein SE. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation 1973; 47: 291-8.

[86] Wainwright CL, Parratt JR. An antiarrhythmic effect of adenosine during myocardial ischaemia and reperfusion. Eur J Pharmacol 1988; 145: 183-94.

[87] Richardt G, Waas W, Kranzhofer R, Mayer E, Schomig A. Adenosine inhibits exocytotic release of endogenous noradrenaline in rat heart: a protective mechanism in early myocardial ischemia. Circ Res 1987; 61: 117-23.

[88] Rubio R, Berne RM, Katori M. Release of adenosine in reactive hyperemia of the dog heart. Am J Physiol 1969; 216: 56-62.

[89] Katori M, Berne RM. Release of adenosine from anoxic hearts. Relationship to coronary flow. Circ Res 1966; 19: 420-5.

[90] Headrick JP, Matherne GP, Berne RM. Myocardial adenosine formation during hypoxia: effects of ecto-5'-nucleotidase inhibition. J Mol Cell Cardiol 1992; 24: 295-303.

[91] Foley DH, Herlihy JT, Thompson CI, Rubio R, Berne RM. Increased adenosine formation by rat myocardium with acute aortic constriction. J Mol Cell Cardiol 1978; 10: 293-300.

[92] Berne RM, Gidday JM, Hill HE, Curnish RR, Rubio R. The interstitial fluid adenosine concentration during altered cardiac metabolism in the dog. Prog Clin Biol Res 1987; 230: 3-11.

[93] Kusachi S, Olsson RA. Pericardial superfusion to measure cardiac interstitial adenosine concentration. Am J Physiol 1983; 244: H458-61.

[94] Olsson RA, Snow JA, Gentry MK. Adenosine metabolism in canine myocardial reactive hyperemia. Circ Res 1978; 42: 358-62.

[95] Olsson RA, Snow JA, Gentry MK, Frick GP. Adenosine uptake by canine heart. Circ Res 1972; 31: 767-78.

[96] Degenring FH, Rubio R, Berne RM. Adenine nucleotide metabolism during cardiac hypertrophy and ischemia in rats. J Mol Cell Cardiol 1975; 7: 105-13.

Adenosine and Arrhythmia Current Pharmaceutical Design, 2015, Vol. 21, No. 8 975

[97] Thomas RA, Rubio R, Berne RM. Comparison of the adenine nucleotide metabolism of dog atrial and ventricular myocardium. J Mol Cell Cardiol 1975; 7: 115-23.

[98] Fox AC, Reed GE, Glassman E, Kaltman AJ, Silk BB. Release of adenosine from human hearts during angina induced by rapid atrial pacing. J Clin Invest 1974; 53: 1447-57.

[99] Wainwright CL, Parratt JR, Van Belle H. The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs. Br J Pharmacol 1993; 109: 592-9.

[100] Parratt JR, Wadsworth RM. The effects of dipyridamole on coronary post-occlusion hyperaemia and on myocardial vasodilatation induced by systemic hypoxia. Br J Pharmacol 1972; 46: 594-601.

[101] Van Belle H. Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine? Cardiovasc Res 1993; 27: 68-76.

[102] Belhassen B, Pelleg A. Electrophysiologic effects of adenosine triphosphate and adenosine on the mammalian heart: clinical and experimental aspects. J Am Coll Cardiol 1984; 4: 414-24.

[103] diMarco JP, Sellers TD, Lerman BB, Greenberg ML, Berne RM, Belardinelli L. Diagnostic and therapeutic use of adenosine in patients with supraventricular tachyarrhythmias. J Am Coll Cardiol 1985; 6: 417-25.

[104] Faulds D, Chrisp P, Buckley MM. Adenosine. An evaluation of its use in cardiac diagnostic procedures, and in the treatment of paroxysmal supraventricular tachycardia. Drugs 1991; 41: 596-624.

[105] Camm AJ, Garratt CJ. Adenosine and supraventricular tachycardia. N Engl J Med 1991; 325: 1621-9.

[106] Bertolet BD, Hill JA. Adenosine: diagnostic and therapeutic uses in cardiovascular medicine. Chest 1993; 104: 1860-71.

[107] Fazekas T, Liszkai G. [Cardiac electrophysiological effect and clinical use of adenosine]. Orv Hetil 1999; 140: 1219-26.

[108] Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy. Current concepts. Drugs 1987; 33: 623-33.

[109] Clarke B, Till J, Rowland E, Ward DE, Barnes PJ, Shinebourne EA. Rapid and safe termination of supraventricular tachycardia in children by adenosine. Lancet 1987; 1: 299-301.

[110] Till J, Shinebourne EA, Rigby ML, Clarke B, Ward DE, Rowland E. Efficacy and safety of adenosine in the treatment of supraventricular tachycardia in infants and children. Br Heart J 1989; 62: 204-11.

[111] Rossi AF, Steinberg LG, Kipel G, Golinko RJ, Griepp RB. Use of adenosine in the management of perioperative arrhythmias in the pediatric cardiac intensive care unit. Crit Care Med 1992; 20: 1107-11.

[112] Overholt ED, Rheuban KS, Gutgesell HP, Lerman BB, DiMarco JP. Usefulness of adenosine for arrhythmias in infants and children. Am J Cardiol 1988; 61: 336-40.

[113] Belardinelli L, Giles WR, West A. Ionic mechanisms of adenosine actions in pacemaker cells from rabbit heart. J Physiol 1988; 405: 615-33.

[114] Engelstein ED, Lippman N, Stein KM, Lerman BB. Mechanism-specific effects of adenosine on atrial tachycardia. Circulation 1994; 89: 2645-54.

[115] Epstein ML, Belardinelli L. Failure of adenosine to terminate focal atrial tachycardia. Pediatr Cardiol 1993; 14: 119-21.

[116] Perelman MS, Krikler DM. Termination of focal atrial tachycardia by adenosine triphosphate. Br Heart J 1987; 58: 528-30.

[117] DiMarco JP, Miles W, Akhtar M, et al. 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 Med 1990; 113: 104-10.

[118] Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983; 93: 21-6.

[119] Ontyd J, Schrader J. Measurement of adenosine, inosine, and hypoxanthine in human plasma. J Chromatogr 1984; 307: 404-9.

[120] Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physiol 1989; 256: C799-806.

[121] Rankin AC, Rae AP, Oldroyd KG, Cobbe SM. Verapamil or adenosine for the immediate treatment of supraventricular tachycardia. Q J Med 1990; 74: 203-8.

[122] Rosales OR, Eades B, Assali AR. Cardiovascular drugs: adenosine role in coronary syndromes and percutaneous coronary interventions. Catheter Cardiovasc Interv 2004; 62: 358-63.

[123] Norton GR, Woodiwiss AJ, McGinn RJ, et al. Adenosine A1 receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart. Am J Physiol 1999; 276: H341-9.

[124] Muller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta 2011; 1808: 1290-308.

[125] Prystowsky EN, Niazi I, Curtis AB, et al. Termination of paroxysmal supraventricular tachycardia by tecadenoson (CVT-510), a novel A1-adenosine receptor agonist. J Am Coll Cardiol 2003; 42: 1098-102.

[126] Wu L, Belardinelli L, Zablocki JA, Palle V, Shryock JC. A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts. Am J Physiol Heart Circ Physiol 2001; 280: H334-43.

[127] Peterman C, Sanoski CA. Tecadenoson: a novel, selective A1 adenosine receptor agonist. Cardiol Rev 2005; 13: 315-21.

[128] Mason PK, DiMarco JP. New pharmacological agents for arrhythmias. Circ Arrhythm Electrophysiol 2009; 2: 588-97.

[129] Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol 2003; 25: 747-71.

[130] Stevenson WG. Current treatment of ventricular arrhythmias: State of the art. Heart Rhythm 2013; 10: 1919-26.

[131] Mor M, Shalev A, Dror S, et al. INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats. J Pharmacol Exp Ther 2013; 344: 59-67.

[132] Chen J, Runyan SA, Robinson MR. Novel ocular antihypertensive compounds in clinical trials. Clin Ophthalmol 2011; 5: 667-77.

[133] Samsel M, Dzierzbicka K. Therapeutic potential of adenosine analogues and conjugates. Pharmacol Rep 2011; 63: 601-17.

[134] Cheung JW, Ip JE, Chung JH, et al. Differential effects of adenosine on pulmonary vein ectopy after pulmonary vein isolation: implications for arrhythmogenesis. Circ Arrhythm Electrophysiol 2012; 5: 659-66.

[135] Datino T, Macle L, Qi XY, et al. Mechanisms by which adenosine restores conduction in dormant canine pulmonary veins. Circulation 2010; 121: 963-72.

[136] McLellan AJ, Kumar S, Smith C, et al. The role of adenosine following pulmonary vein isolation in patients undergoing catheter ablation for atrial fibrillation: a systematic review. J Cardiovasc Electrophysiol 2013; 24: 742-51.

[137] Brunelli M, Raffa S, Grosse A, et al. Residual conduction after pulmonary vein isolation with a circular multielectrode radiofrequency ablation catheter: the role of adenosine and orciprenalin during a prolonged observation time. Int J Cardiol 2013; 168: 4122-31.

[138] Macle L, Khairy P, Verma A, et al. Adenosine following pulmonary vein isolation to target dormant conduction elimination (ADVICE): methods and rationale. Can J Cardiol 2012; 28: 184-90.

[139] Tomcsanyi J, Tenczer J, Horvath L. Unusual effect of adenosine. Int J Cardiol 1995; 49: 89-91.

[140] Mallet ML. Proarrhythmic effects of adenosine: a review of the literature. Emerg Med J 2004; 21: 408-10.

[141] Brodsky MA, Hwang C, Hunter D, et al. Life-threatening alterations in heart rate after the use of adenosine in atrial flutter. Am Heart J 1995; 130: 564-71.

[142] McCollam PL, Uber WE, Van Bakel AB. Adenosine-related ventricular asystole. Ann Intern Med 1993; 118: 315-6.

[143] Silverman AJ, Machado C, Baga JJ, Meissner MD, Lehmann MH, Steinman RT. Adenosine-induced atrial fibrillation. Am J Emerg Med 1996; 14: 300-1.

[144] Strickberger SA, Man KC, Daoud EG, et al. Adenosine-induced atrial arrhythmia: a prospective analysis. Ann Intern Med 1997; 127: 417-22.

[145] Glatter KA, Cheng J, Dorostkar P, et al. Electrophysiologic effects of adenosine in patients with supraventricular tachycardia. Circulation 1999; 99: 1034-40.

[146] Wiener N, Rosenblueth A. The mathematical formulation of the problem of conduction of impulses in a network of connected excitable elements, specifically in cardiac muscle. Arch Inst Cardiol Mex 1946; 16: 205-65.

976 Current Pharmaceutical Design, 2015, Vol. 21, No. 8 Szentmiklósi et al.

[147] Smeets JL, Allessie MA, Lammers WJ, Bonke FI, Hollen J. The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. The role of heart rate, autonomic transmitters, temperature, and potassium. Circ Res 1986; 58: 96-108.

[148] Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 1988; 62: 395-410.

[149] Biaggioni I, Killian TJ, Mosqueda-Garcia R, Robertson RM, Robertson D. Adenosine increases sympathetic nerve traffic in humans. Circulation 1991; 83: 1668-75.

[150] Szegi J, Szentmiklosi AJ, Cseppento A. Adenosine decreases the fibrillation threshold in atrial myocardium. Pol J Pharmacol Pharm 1989; 41: 511-8.

[151] Szekeres L, Papp G. The Effect of Vagal Stimulation and Acetylcholine on the Susceptibility to Fibrillation of the Mammalian Heart at Different Body Temperatures. Acta Physiol Acad Sci Hung 1965; 26: 277-86.

[152] Maling HM, Moran NC. Ventricular arrhythmias induced by sympathomimetic amines in unanesthetized dogs following coronary artery occlusion. Circ Res 1957; 5: 409-13.

[153] Bertolet BD, Hill JA, Kerensky RA, Belardinelli L. Myocardial infarction related atrial fibrillation: role of endogenous adenosine. Heart 1997; 78: 88-90.

[154] Bertolet BD, Eagle DA, Conti JB, Mills RM, Belardinelli L. Bradycardia after heart transplantation: reversal with theophylline. J Am Coll Cardiol 1996; 28: 396-9.

[155] Alboni P, Menozzi C, Brignole M, et al. Effects of permanent pacemaker and oral theophylline in sick sinus syndrome the THEOPACE study: a randomized controlled trial. Circulation 1997; 96: 260-6.

[156] Klaasse EC, Ijzerman AP, de Grip WJ, Beukers MW. Internalization and desensitization of adenosine receptors. Purinergic Signal 2008; 4: 21-37.

[157] Srinivas M, Shryock JC, Dennis DM, Baker SP, Belardinelli L. Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Mol Pharmacol 1997; 52: 683-91.

[158] Albrecht-Kupper BE, Leineweber K, Nell PG. Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signal 2012; 8: 91-9.

[159] Parsons WJ, Stiles GL. Heterologous desensitization of the inhibitory A1 adenosine receptor-adenylate cyclase system in rat adipocytes. Regulation of both Ns and Ni. J Biol Chem 1987; 262: 841-7.

[160] Jacobson KA, von Lubitz DK, Daly JW, Fredholm BB. Adenosine receptor ligands: differences with acute versus chronic treatment. Trends Pharmacol Sci 1996; 17: 108-13.

[161] Willems L, Ashton KJ, Headrick JP. Adenosine-mediated cardioprotection in the aging myocardium. Cardiovasc Res 2005; 66: 245-55.

[162] Berne RM. Adenosine--a cardioprotective and therapeutic agent. Cardiovasc Res 1993; 27: 2.

[163] Mullane K, Bullough D. Harnessing an endogenous cardioprotective mechanism: cellular sources and sites of action of adenosine. J Mol Cell Cardiol 1995; 27: 1041-54.

[164] Szentmiklosi AJ, Cseppento A, Harmati G, Nanasi PP. Novel trends in the treatment of cardiovascular disorders: site- and event- selective adenosinergic drugs. Curr Med Chem 2011; 18: 1164-87.

[165] Yoshida Y, Hirai M, Yamada T, et al. Antiarrhythmic efficacy of dipyridamole in treatment of reperfusion arrhythmias : evidence for cAMP-mediated triggered activity as a mechanism responsible for reperfusion arrhythmias. Circulation 2000; 101: 624-30.

[166] Strauer BE, Heidland UE, Heintzen MP, Schwartzkopff B. Pharmacologic myocardial protection during percutaneous transluminal coronary angioplasty by intracoronary application of dipyridamole: impact on hemodynamic function and left ventricular performance. J Am Coll Cardiol 1996; 28: 1119-26.

[167] Hegedus K, Keresztes T, Fekete I, Molnar L. Effect of i.v. dipyridamole on cerebral blood flow, blood pressure, plasma adenosine and cAMP levels in rabbits. J Neurol Sci 1997; 148: 153-61.

[168] Miyahara M, Imura O, Yokoyama M, Hoshikawa K. Lidoflazine as an antiarrhythmic drug. Tohoku J Exp Med 1969; 97: 95-6.

[169] Bernauer W. Effect of exogenous adenosine deaminase on arrhythmias and the release of adenine nucleotide catabolites in isolated rat hearts with coronary occlusion and reperfusion. Naunyn Schmiedebergs Arch Pharmacol 1991; 344: 544-50.

[170] Gruber HE, Hoffer ME, McAllister DR, et al. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. Circulation 1989; 80: 1400-11.

[171] Galinanes M, Mullane KM, Bullough D, Hearse DJ. Acadesine and myocardial protection. Studies of time of administration and dose-response relations in the rat. Circulation 1992; 86: 598-608.

[172] Goblyos A, Ijzerman AP. Allosteric modulation of adenosine receptors. Purinergic Signal 2009; 5: 51-61.

[173] Kollias-Baker C, Xu J, Pelleg A, Belardinelli L. Novel approach for enhancing atrioventricular nodal conduction delay mediated by endogenous adenosine. Circ Res 1994; 75: 972-80.

[174] Butcher A, Scammells PJ, White PJ, Devine SM, Rose'meyer RB. An allosteric modulator of the adenosine A1 receptor improves cardiac function following ischaemia in murine isolated hearts. Pharmaceuticals (Basel) 2013; 6: 546-56.

[175] Kimatrai-Salvador M, Baraldi PG, Romagnoli R. Allosteric modulation of A1-adenosine receptor: a review. Drug Discov Today Technol 2013; 10: e285-96.

[176] Baraldi PG, Romagnoli R, Pavani MG, et al. Synthesis and biological effects of novel 2-amino-3-naphthoylthiophenes as allosteric enhancers of the A1 adenosine receptor. J Med Chem 2003; 46: 794-809.

[177] Boos CJ, Anderson RA, Lip GY. Is atrial fibrillation an inflammatory disorder? Eur Heart J 2006; 27: 136-49.

[178] Goette A. Atrial fibrillation: an inflammatory disease or a conformational disorder? Can J Cardiol 2012; 28: 529-30.

[179] Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012; 60: 2263-70.

[180] Cronstein BN. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol (1985) 1994; 76: 5-13.

[181] Nakav S, Chaimovitz C, Sufaro Y, et al. Anti-inflammatory preconditioning by agonists of adenosine A1 receptor. PLoS One 2008; 3: e2107.

[182] Milne GR, Palmer TM. Anti-inflammatory and immunosuppressive effects of the A2A adenosine receptor. ScientificWorldJournal 2011; 11: 320-39.

Received: July 2, 2014 Accepted: October 24, 2014