Current Medicinal Chemistry, 2011, 18, 3695-3706 3695 Xanthine Derivatives in the Heart: Blessed or Cursed? A. J. Szentmiklósi*,#,1, Á. Cseppent#,1, R. Gesztelyi2, J. Zsuga3, Á. Körtvély4 , G. Harmati4 and P.P. Nánási4 1Department of Pharmacology and Pharmacotherapy, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary 2Department of Pharmacodynamics, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary 3Department of Neurology, University of Debrecen, Medical and Health Science Center, Debrecen, H-4032, Hungary 4Department of Physiology, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary Abstract: Methylxanthines, such as theophylline, have been used to treat cardiorespiratory disorders, whereas caffeine is the most widely consumed psychoactive agent in various soft drinks. Because of the worldwide use of these drugs and the recently synthesized xanthine derivatives, an intensive research on the cardiac actions of these substances is under progress. This review focuses on the molecular mechanisms involved in the actions of xanthine derivatives with special reference to their adenosine receptor antagonistic properties. The main basic and human studies on the action of xanthines on impulse initiation and conduction, as well as the electrophysiological and mechanical activity of the working myocardium will be overviewed. The potential beneficial and harmful actions of the methylxanthines will be discussed in light of the recent experimental and clinical findings. The pharmacological features and clinical observations with adenosine receptor subtype-specific xanthine antagonists are also the subject of this paper. Based on the adenosine receptor-antagonistic activity of these compounds, it can be raised that xanthine derivatives might inhibit the cardioprotective action of endogenous adenosine on various subtypes (A1, A2A, A2B and A3) of adenosine receptors. Adenosine is an important endogenous substance with crucial role in the regulation of cardiac function under physiological and pathological conditions (preconditioning, postconditioning, ische- mia/reperfusion injury). Recent clinical studies show that acute administration of caffeine or theophylline can inhibit various types of preconditioning in human subjects. There are no human studies, however, for the cardiovascular actions of long-term administration of these drugs. Upregulation of adenosine receptors and increased effectiveness of adenosine receptor-related cardiovascular functions have been observed after long-lasting treatment with methylxanthines. In addition, there are data indicating that blood adenosine level in- creases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine deriva- tives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthi- nes as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted re- actions are minimized. Keywords: Methylxanthines, xanthine derivatives, adenosine, adenosine receptors, subtype-selectivity, risk/benefit ratio. 1. INTRODUCTION phosphodiesterase enzyme and induce mobilization of calcium from the sarcoplasmic reticulum. It is now becoming clearer that the The commonly used methylxanthines theophylline, caffeine and mainstream of the site of actions of methylxanthines are the adeno- theobromine are naturally occurring compounds in various plants. sine receptors, at least, in the therapeutically relevant concentra- These substances are components of most widely consumed bever- tions of 20-50 M [4, 5]. Accordingly, in this paper we discuss the ages, coffee, tea and cocoa. Theophylline and its salts (aminophyl- cardiac actions of methylxanthines when applied in both therapeutic line, choline theophyllinate) or derivatives (enprophylline, doxofyl- and toxic concentrations. We emphasize the cardiac electrophysi- line, bamiphylline) - depicted in Fig. (1) - are used in the therapy of ological effects of xanthines with special reference to antagonistic bronchial asthma and chronic obstructive pulmonary disease actions on adenosine receptors. (COPD), whereas pentoxyphylline in the treatment of peripheral vascular diseases and in the management of cerebrovascular insuf- 2. MECHANISM OF ACTION OF METHYLXANTHINES ficiency, as well as in diabetic neuropathy [1]. Occasionally theo- AND OTHER XANTHINE DERIVATIVES: BASIC STUDIES phylline is applied to prevent sleep apnea in adults. Caffeine is an analeptic and central nervous system stimulant drug being generally 2.1. Basic Studies on Acute Actions of Methylxanthines and used for enhancement of arousal and vigilance, suppression of fa- other Xanthine Derivatives tigue, as well as to shorten reaction time of the motor system. In addition, caffeine has long been used as an adjuvant in combina- Caffeine in millimolar concentrations has been shown to induce tions to potentiate the pharmacological actions of various analgesics various electrophysiological effects on pacemaker fibers and work- such as acetaminophen and acetylsalicylic acid [2, 3]. ing myocardium. These effects display wide interspecies depend- Methylxanthines, like theophylline or caffeine, are also widely ence. Thus, in rabbit sinoatrial nodal cells, caffeine (1 to10 mM) used in cardiology, since these drugs are appropriate medicaments induced a concentration-dependent, atropine-resistant decrease in for treatment of various bradyarrhythmias and disturbances of sinoatrial pacemaker activity. Caffeine increased the slow inward current, reduced the delayed rectifying outward current, and ele- atrioventricular conduction. In some selected cases, theophylline 2+ may be used as classical “ino-dilator” and diuretic [4]. vated the cytoplasmic Ca concentration. Some of the preparations displayed arrhythmias resulting from the caffeine-induced calcium The mechanism of cellular action of methylxanthines is quite overload. The observed sinus bradycardia can also be related to this complex and their action depends on the concentration applied. latter mechanism [6]. In canine cardiac Purkinje fibers, caffeine (0.5 According to the most conventional views, methylxanthines inhibit to 3 mM) induced an oscillatory potential, which could be modu- lated by altering intracellular calcium concentration. This oscilla- tory potential explained the arrhythmias observed in Purkinje fibers *Address correspondence to this author at the Department of Pharmacology and Phar- [ ] macotherapy, University of Debrecen, Medical and Health Science Center, H-4012 7 . In human atrial fibers theophylline (0.1 to 1 mM) was shown to Debrecen, Hungary; Tel: +36 52 411717 ext. 55018; Fax: +36 52 427899; E-mail: increase the rate of phase 4 depolarization and the amplitude of the [email protected] oscillatory potential during diastole and induced the development of #These authors contributed equally to this work. spontaneous slow action potentials. These findings represent the 0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. 3696 Current Medicinal Chemistry, 2011 Vol. 18, No. 24 Szentmiklósi et al. O H N O HN CH O 3 H3C N H N O N N H3C N N O N N O N N CH3 CH3 CH3 Theophylline Caffeine Enprophylline CH3 OH O N O O CH O 3 O O N H C H3C N H3C N 3 N N N N O N N O N N O N CH 3 CH CH3 3 Pentoxyphylline Doxofylline Bamiphylline Fig. (1). Chemical structures of most frequently used methylxanthine drugs. major electrophysiological basis helping to understand the theo- specific adenosine receptor activation. All subtypes of adenosine phylline-induced atrial ectopic activity [8]. In working myocardium receptors are available in the heart [24]. A1 adenosine receptors are 2+ caffeine stimulated the L-type Ca -current (ICa) [9, 10]. This effect negatively coupled to adenylyl cyclase, and are responsible for the can be ascribed to the ability of caffeine to activate the ryanodine reduction of sinoatrial rate, AV-conduction, atrial contractile force, channels in the sarcoplasmic reticulum. Caffeine is known to in- attenuation of the positive inotropic effect of catecholamines, as crease the calcium-induced calcium release, amplifying thus the well as for the protection against myocardial ischemia/reperfusion slow inward current [11]. In contrast, there are studies indicating an injury. A2A receptors are positively coupled to adenylyl cyclase. inhibitory action of caffeine on ICa [12, 13]. In rat ventricular myo- They are expressed in rat ventricular myocardium and are known to cytes, Varro et al. [14] found that high concentration (20 mM) of counteract some A1 adenosine receptor-mediated anti-adrenergic caffeine reduced the amplitude of the inward rectifier potassium actions [25]. A2B adenosine receptors couple positively to adenylyl and inward calcium currents. Zhang et al. [15] described a caffeine- cyclase, and mitogen-activated protein kinase. These receptors were activated large-conductance plasma membrane cation channel in suggested to modulate cellular hypertrophy [26]. A3 receptors, like cardiac myocytes. It was suggested that this can be an additional A1 adenosine receptors, are negatively linked to adenylyl cyclase. mechanism by which caffeine and theophylline may contribute to Their activation could inhibit the -adrenergic receptor activation- generation of cardiac arrhythmias. induced enhancement of cAMP, as well as provides tolerance