Download Xanthine Derivatives in the Heart: Blessed or Cursed?

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
1
Department of Pharmacology and Pharmacotherapy, University of Debrecen, Medical and Health Science Center, Debrecen,
H-4012, Hungary
2
Department of Pharmacodynamics, University of Debrecen, Medical and Health Science Center, Debrecen, H-4012, Hungary
3
Department of Neurology, University of Debrecen, Medical and Health Science Center, Debrecen, H-4032, Hungary
4
Department 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, A 2B 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, ischemia/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 increases after long-term caffeine administration. Since the salutary actions (and also the adverse reactions) of a number of xanthine derivatives are repeatedly shown, the main goal is the development of novel structures that mimic the actions of the conventional methylxanthines as lead compounds, but their adenosine receptor subtype-specificity is higher, their water solubility is optimal, and the unwanted reactions are minimized.
Keywords: Methylxanthines, xanthine derivatives, adenosine, adenosine receptors, subtype-selectivity, risk/benefit ratio.
1. INTRODUCTION
The commonly used methylxanthines theophylline, caffeine and
theobromine are naturally occurring compounds in various plants.
These substances are components of most widely consumed beverages, coffee, tea and cocoa. Theophylline and its salts (aminophylline, choline theophyllinate) or derivatives (enprophylline, doxofylline, bamiphylline) - depicted in Fig. (1) - are used in the therapy of
bronchial asthma and chronic obstructive pulmonary disease
(COPD), whereas pentoxyphylline in the treatment of peripheral
vascular diseases and in the management of cerebrovascular insufficiency, as well as in diabetic neuropathy [1]. Occasionally theophylline is applied to prevent sleep apnea in adults. Caffeine is an
analeptic and central nervous system stimulant drug being generally
used for enhancement of arousal and vigilance, suppression of fatigue, as well as to shorten reaction time of the motor system. In
addition, caffeine has long been used as an adjuvant in combinations to potentiate the pharmacological actions of various analgesics
such as acetaminophen and acetylsalicylic acid [2, 3].
Methylxanthines, like theophylline or caffeine, are also widely
used in cardiology, since these drugs are appropriate medicaments
for treatment of various bradyarrhythmias and disturbances of
atrioventricular conduction. In some selected cases, theophylline
may be used as classical “ino-dilator” and diuretic [4].
The mechanism of cellular action of methylxanthines is quite
complex and their action depends on the concentration applied.
According to the most conventional views, methylxanthines inhibit
*Address correspondence to this author at the Department of Pharmacology and Pharmacotherapy, University of Debrecen, Medical and Health Science Center, H-4012
Debrecen, Hungary; Tel: +36 52 411717 ext. 55018; Fax: +36 52 427899; E-mail:
[email protected]
#
These authors contributed equally to this work.
0929-8673/11 $58.00+.00
phosphodiesterase enzyme and induce mobilization of calcium from
the sarcoplasmic reticulum. It is now becoming clearer that the
mainstream of the site of actions of methylxanthines are the adenosine receptors, at least, in the therapeutically relevant concentrations of 20-50 M [4, 5]. Accordingly, in this paper we discuss the
cardiac actions of methylxanthines when applied in both therapeutic
and toxic concentrations. We emphasize the cardiac electrophysiological effects of xanthines with special reference to antagonistic
actions on adenosine receptors.
2. MECHANISM OF ACTION OF METHYLXANTHINES
AND OTHER XANTHINE DERIVATIVES: BASIC STUDIES
2.1. Basic Studies on Acute Actions of Methylxanthines and
other Xanthine Derivatives
Caffeine in millimolar concentrations has been shown to induce
various electrophysiological effects on pacemaker fibers and working myocardium. These effects display wide interspecies dependence. Thus, in rabbit sinoatrial nodal cells, caffeine (1 to10 mM)
induced a concentration-dependent, atropine-resistant decrease in
sinoatrial pacemaker activity. Caffeine increased the slow inward
current, reduced the delayed rectifying outward current, and elevated the cytoplasmic Ca2+ concentration. Some of the preparations
displayed arrhythmias resulting from the caffeine-induced calcium
overload. The observed sinus bradycardia can also be related to this
latter mechanism [6]. In canine cardiac Purkinje fibers, caffeine (0.5
to 3 mM) induced an oscillatory potential, which could be modulated by altering intracellular calcium concentration. This oscillatory potential explained the arrhythmias observed in Purkinje fibers
[7]. In human atrial fibers theophylline (0.1 to 1 mM) was shown to
increase the rate of phase 4 depolarization and the amplitude of the
oscillatory potential during diastole and induced the development of
spontaneous slow action potentials. These findings represent the
© 2011 Bentham Science Publishers Ltd.
3696 Current Medicinal Chemistry, 2011 Vol. 18, No. 24
Szentmiklósi et al.
O
O
O
H3C
H
N
N
O
H3C
O
N
N
CH3
N
N
H
N
HN
O
N
N
N
N
CH3
CH3
Caffeine
Enprophylline
CH3
Theophylline
CH3
OH
O
O
O
CH3
O
H3C
O
O
N
N
N
N
H3C
Pentoxyphylline
O
H3C
N
N
N
N
O
CH3
CH3
Doxofylline
N
N
O
N
N
N
CH3
Bamiphylline
Fig. (1). Chemical structures of most frequently used methylxanthine drugs.
major electrophysiological basis helping to understand the theophylline-induced atrial ectopic activity [8]. In working myocardium
caffeine stimulated the L-type Ca2+-current (ICa) [9, 10]. This effect
can be ascribed to the ability of caffeine to activate the ryanodine
channels in the sarcoplasmic reticulum. Caffeine is known to increase the calcium-induced calcium release, amplifying thus the
slow inward current [11]. In contrast, there are studies indicating an
inhibitory action of caffeine on ICa [12, 13]. In rat ventricular myocytes, Varro et al. [14] found that high concentration (20 mM) of
caffeine reduced the amplitude of the inward rectifier potassium
and inward calcium currents. Zhang et al. [15] described a caffeineactivated large-conductance plasma membrane cation channel in
cardiac myocytes. It was suggested that this can be an additional
mechanism by which caffeine and theophylline may contribute to
generation of cardiac arrhythmias.
It is important to take into account that these changes occur in a
concentration range of 1 to 20 mM of methylxanthines. This range
is well above those xanthine concentrations (20-50 M) which can
be reached during therapeutic interventions or by consuming caffeine-containing soft drinks. The cardiac actions of methylxanthines
could not be explained by their phosphodiesterase inhibiting action
or by mobilization of intracellular calcium, since these effects of
methylxanthines are very slight at concentrations below 100 M.
On the other hand, methylxanthines have been shown to antagonize
adenosine receptors effectively within their therapeutic concentration range [16]. Therefore, it is conceivable that cardiac activity of
methylxanthines can be related to their antagonistic actions directed
to endogenous adenosinergic signalization [17].
Adenosine is an endogenous, crucial signaling purine nucleoside that plays prominent role in regulation of cardiovascular function, having also an important role in pathogenesis of various cardiovascular diseases. Adenosine is much implicated in the control
of local blood flow of various organs [18], regulation of cardiac
pacemaker activity, AV conduction, myocardial contractility, and
cardioprotection [19-23]. Adenosine acts through G protein-coupled
receptors on the target cells. Until recently, four subtypes of adenosine, namely A1, A2A, A2B and A3, have been identified structurally,
functionally and pharmacologically. These adenosine receptors
were characterized on the basis of their specific pharmacological
profile (rank order of potency of agonists and antagonists), G protein coupling, and signaling mechanism involved in the subtype-
specific adenosine receptor activation. All subtypes of adenosine
receptors are available in the heart [24]. A1 adenosine receptors are
negatively coupled to adenylyl cyclase, and are responsible for the
reduction of sinoatrial rate, AV-conduction, atrial contractile force,
attenuation of the positive inotropic effect of catecholamines, as
well as for the protection against myocardial ischemia/reperfusion
injury. A2A receptors are positively coupled to adenylyl cyclase.
They are expressed in rat ventricular myocardium and are known to
counteract some A1 adenosine receptor-mediated anti-adrenergic
actions [25]. A2B adenosine receptors couple positively to adenylyl
cyclase, and mitogen-activated protein kinase. These receptors were
suggested to modulate cellular hypertrophy [26]. A3 receptors, like
A1 adenosine receptors, are negatively linked to adenylyl cyclase.
Their activation could inhibit the -adrenergic receptor activationinduced enhancement of cAMP, as well as provides tolerance
against hypoxic injury [27]. To understand all cardiac actions of
methylxanthines, it is necessary to shortly survey the main effects
of adenosine on the cardiac pacemakers, conduction systems and
the working myocardium.
Regarding the action of adenosine on impulse initiation and
conduction, the first described action of adenosine was slowing of
the heart rate [28]. In spontaneously beating isolated right atrial
myocardium, His bundles, and Purkinje fibers of guinea pigs,
adenosine showed a characteristic suppressive effect on the spontaneous firing rate in these specific pacemaker cells [29-35]. A1
adenosine receptor activation enhanced the inward rectifier potassium current (IK-Ado), and consequently hyperpolarized the cell
membrane resulting in reduction of the slope of phase 4 depolarization [36-38]. Adenosine has also been reported to inhibit the pacemaker current (If) in sinoatrial and AV nodal cells [39-41]. In human, Honey and his colleagues were the first to describe in 1930
[42] that adenosine induced sinus bradycardia. Endogenously released adenosine might have a role in hypoxia- or ischemia-induced
bradycardia, since the adenosine receptor antagonist aminopylline
antagonized the hypoxia-induced suppression of sinoatrial pacemaker activity in spontaneously beating guinea pig right atrial
preparations. As for humans, Watt has proposed that adenosine
might be involved in bradyarrhythmias related to sick sinus syndrome [43, 44].
Drury and Szent-Györgyi were the first to identify adenosineinduced heart block [28]. Later, Stafford observed that adenosine
Xanthine Derivatives in the Heart
Adenosine is thought to be exerted a strong depressant effect on
atrial myocardial contractility. The negative inotropic effect of
adenosine has been described in electrically driven rat [49], guinea
pig, and human atrial preparations [50-53]. The negative inotropic
effect in atrial myocardium is related to the marked shortening of
action potentials [22, 49, 51, 54, 55]. Based on microelectrode recordings and 42K flux measurements, Jochem and Nawrath were the
first to report that adenosine activated a potassium conductance
[55]. Belardinelli and Isenberg, using voltage-clamp technique in
single atrial myocytes, showed that the adenosine-activated conductance was an inwardly rectifying potassium current [36]. It was also
revealed that the adenosine- and acetylcholine-activated conductances are identical, and these channels are associated with the receptors via a pertussis toxin-sensitive G-protein. Schrader et al.
reported that adenosine reduced the rate of rise and amplitude of the
slow action potential in guinea pig atrial preparations [56]. Now it is
clear that the mechanism of the depressant effects of adenosine on
the atrial myocardium is related to activation of the inwardlyrectifying potassium current (IK-Ado) and a blockade of the slow
inward current mediated by L-type Ca2+ channels [57].
Adenosine exerts quite different actions on contractility in atrial
and ventricular myocardium. Under baseline conditions, adenosine
had no negative inotropic action in ventricles - it displayed rather a
moderate positive inotropic effect [58-64]. Importantly, adenosine
had no effect on action potential duration or baseline L-type calcium current [65]. In contrast, in ventricular myocardium when
adenylate cyclase was previously activated using various compounds, including isoprenaline, histamine and dopamine, adenosine
displayed a negative inotropic action [58, 63, 64, 66-68]. Under
these conditions adenosine or adenosine analogues attenuated all
catecholamine-stimulated outward and inward currents. With the
exception of rat and ferret, no adenosine-activated potassium current can be demonstrated in ventricular myocardium [39]. In addition, the anti- adrenergic action of adenosine is due to an inhibition of adenylate cyclase activity with the concomitant reduction of
cAMP content [10, 28, 29, 45]. On the other hand, adenosine has
been shown to exert significant anti-adrenergic effect on myocardial preparations [64, 66]. Accordingly, there is a concept that
adenosine acts as a negative feedback modulator of -adrenoceptormediated responses in the heart [64, 66]. Although ventricular myocardium contains primarily A1 adenosine receptors, there are studies
showing that A2A and A3 adenosine receptors are also expressed in
ventricular myocytes [24].
Accordingly, methylxanthines are capable to antagonize the actions of both exogenous and endogenous adenosine. The competitive antagonism between methylxanthines and exogenous adenosine
in various cardiac functions has long been established [69-71].
A great mass of experimental evidence is available for establishing the ability of methylxanthines to antagonize the effects of
endogenous adenosine accumulated in certain conditions, like hypoxia, ischemia, or increased metabolic activity. Regarding atrioventricular conduction, Belardinelli et al. [72] demonstrated that
3697
adenosine, like hypoxia, exerted a concentration-dependent prolongation of AV conduction in perfused guinea pig heart. Actions on
conduction delay induced by both hypoxia and adenosine could be
antagonized by aminophylline, an adenosine receptor antagonist.
Belardinelli et al. [72] finally suggested that endogenously released
adenosine might play an important role in AV conduction disturbances also in case of acute hypoxia. Similar conclusions have been
drawn in other studies [73, 74].
In our previously reported experiments [75], sinoatrial pacemaker activity of spontaneously beating guinea pig left atria was
recorded using extracellular electrodes. During moderate hypoxia,
the sinoatrial firing rate gradually decreased. This bradycardia was
effectively antagonized by aminophylline, while enhanced in the
presence of the adenosine deaminase inhibitor coformycin and the
membrane purine transport uptake blocker dipyridamole, indicating
the crucial role of the accumulated adenosine in the sinus bradycardia occurring under hypoxic conditions.
A similar experiment is presented in Fig. (2), using another xanthine-type adenosine receptor antagonist, 8-p-(sulphophenyl)theophylline. This xanthine prevented the moderate hypoxia-induced
decrease in sinoatrial pacemaker activity practically completely. As
this compound acts on only at extracellular sites, therefore an additional inhibitory action of enzyme phosphodiesterase can be excluded.
120
% of pre-hypoxia control
caused a concentration-dependent atrioventricular conduction block
in guinea pig hearts [45]. Adenosine is also capable to induce an
impaired or blocked of atrioventricular nodal conduction in humans
[42, 46]. This is generally a short-lived, not too serious, adverse
reaction, but prolonged complete heart block requiring intubation
and temporary pacing has also been reported [47]. A1 adenosine
receptors are abundantly expressed in the AV junction. Adenosine
acts on the proximal part of atrioventricular junction (atrio-nodal
region and nodal region), whereas no effect was observed on the
nodal-His bundle [48]. In the negative dromotropic effect of adenosine, activation of the inward rectifier potassium current and the
concomitant hyperpolarization of the cell membrane may have a
crucial role. In addition, inhibition of L-type calcium channels has
also been a suggested as underlying mechanism [39].
Current Medicinal Chemistry, 2011 Vol. 18, No. 24
*
**
50
60
100
**
**
80
untreated
60
40
8-SPT
20
0
10
20
30
40
70
80
90
minutes during hypoxia
Fig. (2). Action of 50 M 8-p-(sulphophenyl)theophylline (8-SPT) on the
moderate hypoxia-induced decrease in sinoatrial pacemaker activity of
spontaneously beating guinea pig right atria. Asterisks indicate significant
differences between the 8-SPT treated (n=6) and the untreated control (n=9)
groups.
In electrically stimulated guinea pig atria, under normoxic conditions, theophylline induced a significant increase of contractile
force within a concentration range of 0.1-1 mM, which is higher
than usual adenosine receptor-antagonist concentrations [76]. According to Collis et al. [77], the positive inotropic actions of theophylline and enprophylline were not due to adenosine receptor
blockade, but rather to inhibition of phosphodiesterase. According
to experiments of Bellemann and Scholz [78], the positive inotropic
actions of high concentration (0.6 mM) of theophylline can be associated with an increase of sarcolemmal calcium influx and an action
on intracellular calcium binding or storage sites. In electrically
driven left atrial preparations of guinea pigs, adenosine reduced the
contractile force and shortened the duration of intracellularly re-
3698 Current Medicinal Chemistry, 2011 Vol. 18, No. 24
Szentmiklósi et al.
corded action potentials. The similarity between the adenosine- and
the hypoxia-induced alterations of myocardial electrical and mechanical activities is striking, since both the adenosine- and hypoxia-induced changes could readily be prevented by aminophylline. Extreme changes in action potential morphology due to longlasting hypoxia could also be reversed by aminophylline. On the
basis of these results it is assumed that the increased tissue level of
endogenous adenosine in acute myocardial hypoxia might contribute to functional impairment of atrial myocardium [21]. In normoxic conditions, methylxanthines, in therapeutically applied concentrations, do not alter or minimally affect the functional activity
of myocardium and pacemaker tissues. It can be supposed that
stimulatory actions of methylxanthines applied in therapeutic concentrations occur only under pathological conditions (e.g. hypoxia,
ischemia), when endogenous tissue adenosine levels are substantially elevated.
2.2. Basic Studies on Chronic Actions of Xanthine Derivatives
In contrast to the extensive studies performed on the regulation
of CNS adenosine receptors, there is only limited information
available on the effect of chronic methylxanthine treatment on the
cardiovascular action of adenosine. In the study by Wu et al. [79]
the action of a 2-week theophylline treatment on myocardial A 1
adenosine receptors was investigated. Cardiac adenosine receptors
were upregulated by chronic exposure to theophylline and this
upregulation was accompanied by an increased sensitivity of ventricular myocytes to the electrophysiological and biochemical effects of adenosine receptor agonists. Similarly, chronic (2 weeks)
theophylline treatment resulted in upregulation of atrial and ventricular A1 adenosine receptors in rats [80]. It must be noted, however, that only the indirect, antiadrenergic, negative inotropic and
chronotropic effects of adenosine receptor agonist on atrial muscle
were sensitized, but the direct cardioinhibitory actions were not
altered. Chronic caffeine consumption (3 weeks) potentiated the A 2
adenosine receptor-related hypotensive action of adenosine in rats
[81]. According to Varani et al. [82], repeated caffeine administration upregulated human platelet adenosine A2A receptors, which is
accompanied with an increased antiaggregatory action of the A2A
adenosine receptor agonist 2-hexenyl-5’-N-ethylcarboxamidoadenosine. Similar results were obtained also in rat platelets [83].
Interestingly, in an experiment with repeated (23 days) administration of a selective A1 adenosine receptor antagonist KW-3902 (8(noradamantan-3-yl)-1,3-dipropylxanthine) Kusaka and Karasawa
[84] failed to observe any alteration in the A1 adenosine-receptorrelated bradycardic action of 5’-N-ethylcarboxamidoadenosine
(NECA).
In our experiments, the actions of long-term oral caffeine treatment were studied on the electrical and mechanical activity of A 1
adenosine receptor selective N6-cyclopentyladenosine (CPA) on
guinea pig atrial myocardium, as well as on the antagonistic action
of methylxanthines on the CPA-induced decrease of mechanical
activity in atrial myocardium. Slow action potentials were generated in potassium-depolarized (25 mM) guinea pig atrial muscles
treated by 1 M isoproterenol. CPA decreased the rate of rise and
the duration of slow action potentials (Fig. 3, Table 1) in a concentration-dependent manner. A very strong sensitization in the CPAinduced electrophysiological changes was observed after a 2 week
caffeine treatment.
On the basis of these experiments it can be suggested that after
long-lasting caffeine treatment a strong sensitization develops in the
CPA-induced depression of slow Ca2+ influx and outward K+ outflow. It is thought that under these conditions Vmax represents the
slow inward Ca2+ current, whereas duration of slow action potential
is related to the outward potassium current [56]. In these experiments, guinea pigs were fed with caffeine for 10 weeks, their average serum caffeine concentration was 42.3 ± 3.6 M. In electrically
driven left atrial preparations, sensitization to CPA-induced decrease of mechanical activity developed. Its maximum was observed at week 2 of caffeine treatment, then the potency ratio moderately diminished (Table 1). From week 2, the Emax values were
also elevated in atrial muscles of caffeine-treated groups. It is noteworthy, that at week 10 of caffeine treatment a moderate tolerance
developed in the adenosine-antagonistic action of various methylxanthines (e.g. theophylline, caffeine, and DPCPX), i.e. their antiadenosine pA2 values were reduced. From these studies, an upregulation of A1 adenosine receptors due to chronic caffeine treatment,
resulting in alterations in electrical and mechanical parameters of
atrial myocardium, can be concluded.
3. HUMAN STUDIES
There are a number of early reports, indicating that the resting
sinus frequency or the increase during exercise fails to alter significantly after therapeutic doses of caffeine [85]. Interestingly, in various pathological states or in healthy volunteers at various submaximal and maximal exercise intensities, when tissue concentration of endogenous adenosine elevates, methylxanthines exert noticeable effects on the sinoatrial pacemaker. It is suggested by Watt
[43] that sick sinus syndrome is an adenosine-mediated disease. In
this syndrome, oral theophylline proved to be efficacious in increasing sinus rate at rest and during exercise, and also to reduce cardiac
pauses [86, 87]. In a randomized, controlled trial (The THEOPACE
SOLVENT-TREATED
CAFFEINE-TREATED
40
40
30
control
20
Membrane potential (mV)
Membrane potential (mV)
30
CPA 30 nM
10
CPA 100 nM
0
-10
CPA 300 nM
-20
-30
-40
control
20
10
CPA 1 nM
0
-10
CPA 10 nM
-20
CPA 30 nM
-30
-40
-50
-50
0
50
100
Time (ms)
150
200
0
50
100
150
200
Time (ms)
Fig. (3). CPA-induced, concentration-dependent depression of maximum velocity of depolarization (Vmax) and shortening of the duration of slow action potentials generated in guinea pig atrial trabeculae depolarized by 25 mM potassium and treated with 1 M isoproterenol. The preparations were stimulated at a
frequency of 0.5 Hz, transmembrane potentials were recorded using conventional sharp microelectrodes.
Xanthine Derivatives in the Heart
Table 1.
Current Medicinal Chemistry, 2011 Vol. 18, No. 24
3699
Effects of Long-Term Caffeine Treatment on the CPA-Induced Alterations in the Mechanical and Electrical Activity of Guinea Pig
Atrial Myocardium
Parameter
Solvent-treated
Caffeine-treated
pD2
7.73 ± 0.10
8.35 ± 0.06*
Emax
89.5 ± 3.5
92.8 ± 2.5
n
5
6
Week 1
4.17
Concentration ratio
Week 2
pD2
7.54 ± 0.24
8.43 ± 0.04**
Emax
83.5 ± 3.2
93.0 ± 3.2*
n
6
6
Concentration ratio
37.8 ± 4.8
7.76
Vmax (% reduction)
31.0 ± 5.5
95.7 ± 1.8**
APD75 (% shortening)
5
69.7 ± 9.6*
n
4
Week 6
pD2
7.78 ± 0.10
8.58 ± 0.08*
Emax
90.0 ± 1.6
95.2 ± 1.8
n
5
6
Concentration ratio
6.31
Week 10
pD2
7.86 ± 0.08
8.55 ± 0.07*
Emax
85.8 ± 2.4
97.3 ± 1.1*
n
5
4
Concentration ratio
4.90
Data are mean values ± S.E.M, EC50 = the concentration producing half-maximum response (its negative based logarithm: pD2), Emax = maximum effect expressed in % of pre-CPA
contractile force, n = number of experiments, Vmax = rate of rise of depolarization, APD75 = duration of action potential at 75% of repolarization. Changes in Vmax and APD75 were
measured at 10 nM CPA concentration. Concentration ratios denote the ratios of EC50 values of CPA concentration-response curves (solvent-treated versus caffeine-treated). Asterisks indicate significant differences between the caffeine-treated and the solvent-treated control groups.
Study) it was, however, shown that oral theophylline reduced only
the minor symptomes of sick sinus syndrome, while was not effective in patients suffering from severe forms of the disorder [88].
Human electrophysiological studies are also available to demonstrate that oral theophylline suppressed the symptoms in sick sinus
syndrome [89, 90]. Benditt et al. [90] reported that theophylline
treatment was useful in young patients with recurrent symptomatic
bradyarrhythmias. Furthermore, it was suggested that theophylline
might be a reasonable alternative strategy in the treatment of
chronic symptomatic bradycardia in the elderly [91, 92].
Sinus node dysfunction, primarily sinus bradycardia, is frequently associated with heart transplantation [93]. Bertolet and his
coworkers [94] observed that use of theophylline for posttransplantation bradyarrhythmias was efficient in increasing the heart rate
and reduced the need for implantation of a permanent pacemaker.
Reversibility of prolonged chronotropic dysfunction by theophylline and aminophylline following orthotopic cardiac transplantation
was also reported by a number of investigators [95-97]. Oral or
intravenous theophylline proved to be effective in not only sinus
node disturbances, but also in abnormal impulse conduction. Thus,
Alboni et al. [97] described that oral theophylline represents a valid
therapy in most patients with atrial fibrillation associated with a
slow ventricular response. Intravenous theophylline proved to be a
useful method in the management of bradycardia secondary to AV
block and offers a pharmacological alternative to patients where
other pharmacological strategies or cardiac pacemaker implantation
may be contraindicated [98]. An interesting observation was reported by Bertolet et al. [99], who demonstrated the effectiveness of
theophylline in atrial fibrillation due to adenosine accumulation in
acute myocardial infarction. After application of theophylline, a
rapid (< 5 min) and long-term conversion of atrial fibrillation to
sinus rhythm was observed. These findings highlighted the role of
endogenous adenosine in development of atrial fibrillation and the
possibility of an adenosine antagonist-based therapy. As theophylline is not a specific adenosine receptor antagonist, it is hopeful that
A1 adenosine receptor selective antagonists (e.g. synthetic methylxanthines) can be more efficient drugs to terminate this type of atrial
fibrillation [74]. It is noteworthy that after caffeine consumption
different changes in sinus rhythm were observed in healthy humans
exposed to various submaximal and maximal exercise intensities.
Thus, some investigators reported that caffeine increases the heart
rate under these circumstances [100-103]. Recently, McClaran and
Wetter [104] reported that in non-habitual caffeine users, low doses
of caffeine decreased the heart rate during submaximal exercise, but
not at near maximal and maximal exercise. It is tempting to suppose
that because of the imbalance between oxygen requirement and
consumption in maximal physical exercise, endogenous adenosine
release can substantially be increased. In this case caffeine might
counterbalance the endogenous adenosine-related suppression of
sinoatrial pacemaker activity.
There are conflicting reports available on the possible arrhythmogenic action of caffeine or theophylline. According to a metaanalysis, moderate consumption of caffeine does not increase the
frequency or severity of cardiac arrhythmias in healthy persons, in
patients with ischemic heart disease, or in ones having pre-existing
serious ventricular ectopy. There is an increase, however, in the
frequency of ventricular extrasystoles in heavy coffee consumers
drinking 9 or more cups daily [105]. It was recently found that
moderate tea intake can be associated with a lower prevalence,
while higher coffee consumption with a slightly higher prevalence
of ventricular arrhythmias in patients hospitalized with acute myocardial infarction [106]. According to the Danish Diet, Cancer, and
Health Study [107], in which 47 949 subjects were participated,
consumption of caffeine was not associated with an elevated risk of
3700 Current Medicinal Chemistry, 2011 Vol. 18, No. 24
Szentmiklósi et al.
atrial fibrillation or flutter. Similarly, at modest dose of caffeine, no
action on the incidence of ventricular arrhythmia could be observed
in patients with ventricular tachycardia or fibrillation [108, 109].
postglomerular and preglomerular vessels. Adenosine constricts the
preglomerular vessels by activation of A1 adenosine receptors,
whereas exerts a vasodilator action on the postglomerular arterioles
by stimulation of A2 receptors [120]. Activation of A1 receptors
decreases renal perfusion pressure, glomerular filtration, and tubular sodium reabsorption [121]. It is supposed that adenosine may
play a role in the kidney-mediated fluid retention in heart failure
[122]. In this case, use of selective A1 adenosine receptor antagonists might provide therapeutic benefits in the setting of congestive
heart failure. At present, one of the primary approaches of treatment
of heart failure is diuretic therapy. On the basis of clinical experiences, however, it became clear that the generally applied diuretics
(e.g. furosemide) may reduce glomerular filtration rate in patients
suffering from heart failure [120, 123]. In contrast, selective blockade of A1 adenosine receptors by CVT-124 was shown to reduce
afferent arteriole pressure, increase the urinary flow and sodium
excretion [124, 125]. It is logical to assume that treatment with selective A1 adenosine antagonists can be more effective than the
conventional diuretic therapy.
Regarding the effects of methylxanthines on the working myocardium, the picture is quite complex. Conrad and Prosnitz [110]
studied the cardiovascular actions of aminophylline-infusion in
healthy male volunteers and found that aminophylline exerted a
mild positive inotropic effect, but this action could be prevented by
pretreatment with the -adrenergic receptor antagonist metoprolol
or propranolol. The hemodynamic action of intravenously applied
aminophylline was also studied in healthy human subjects and no
significant improvement was found on cardiac performance during
tread-mill exercise after using of the compound [111]. These findings are in good agreement with the further study of Conradson
using theophylline and enprophylline [112]. According to the hemodynamic studies of Parker et al. [113], aminophylline was effective
to increase cardiac output in patients suffering from heart failure,
but no change was observed in patients with cor pulmonale [114] or
chronic obstructive pulmonary disease [115].
The chemical structures of some novel A1 adenosine receptor
selective compounds are presented in Fig. (4). The newest drug in
this category is rolofylline (KW-3902). In a randomized, placebocontrolled, dose-finding study (PROTECT Pilot Study), it was observed that A1 adenosine receptor blockade with rolofylline could
prevent renal impairment in patients with acute heart failure and
positively affected the acute symptoms as well as the 60 days outcome [126]. The large clinical trial, PROTECT, began in May 2007
and was completed in January 2009. 2033 patients from 173 sites of
19 countries were recruited in this study. The results were disappointing as in the larger trial the benefits observed in the PROTECT
Pilot Study could not be replicated. Rolofylline showed no difference from placebo regarding the primary end-points in patients with
acute heart failure. In the study, there was a trend toward a lower
incidence of serious adverse cardiac side reactions, but the incidence of neurological events (seizures and strokes) were higher. As
a consequence, the drug has been dropped from development [127129]. The clinical trial with another A1 adenosine receptor-selective
blocker, naxifylline was also discontinued [130]. At present, it is not
clear whether the basic principle is a pitfall or there might be problems with the physicochemical properties of the investigated drugs?
The resolution of this issue should be very important for the future
Theophylline and aminophylline were extensively used over the
last 70 years to increase inotropy in patients suffering from heart
failure [113, 116], and to treat patients with bronchial asthma [117].
However, because of the narrow therapeutic ratio and due to its
cardiac, gastroenteric and CNS side effects, theophylline has lost
popularity in the last decades. According to current AHA and ESC
guidelines, the two primary pharmacological approaches in symptomatic heart failure are ACE inhibitors/ARBs and diuretics. Theophylline exerts a slight positive inotropic action combined with a
good vasodilator activity, therefore, it can be an ideal drug for combined inotropic and vasodilator treatment of heart failure. In addition, theophylline and its derivatives have also moderate diuretic
activity based on adenosine receptor antagonism [118], decreasing
thus the circulating blood volume and preload of the heart. Endogenous adenosine was also shown to play an important role in pathogenesis of heart failure. Plasma adenosine levels are increased in
patients with heart failure in parallel with the severity of the disease
[119]. In the nephron, A1 and A2 adenosine receptors are widely
distributed and they have significant functional role. Adenosine can
influence the glomerular filtration rate, renal hemodynamics, and
the tubuloglomerular feedback. This purine nucleoside reduces
glomerular filtration by inducing selective vasoactive actions on the
O
H3C
N
O
N
O
O
H
N
H3C
H
N
N
N
O
O
N
Naxifylline (BG-9719, CVT-124)
Rolofylline (KW3902, NAX)
O
OH
O
H3C
H
N
N
O
N
N
CH3
CH3
DPCPX (CPX)
H
N
N
N
N
CH3
H3C
O
H3C
N
H
N
N
O
N
CH3
Toponafylline (BG-9928)
Fig. (4). Chemical structures of DPCPX and new A1 adenosine receptor selective antagonists.
N
OH
PSB-36
O
Xanthine Derivatives in the Heart
trends of drug development. Currently there is only one A1 receptor-selective xanthine derivative, toponafylline under clinical trial
for treatment of heart failure [130].
4. CURRENT PROBLEMS AND FUTURE PERSPECTIVES
Independently of the above mentioned facts, it appears that
theophylline receives a renewed attention as according to a number
of studies. This drug - applied in relatively low doses - was able to
exert significant anti-inflammatory action in patients with bronchial
asthma and chronic obstructive pulmonary disease [117, 131-135].
On the basis of this recognition, a new era of use of methylxanthines may start, the significance of which could affect not only the
treatment conceptions of cardiorespiratory diseases, but also the
synthesis of new and more effective methylxanthines. When considering the ongoing and future use of methylxanthines, we should
take into account a number of issues. According to the title of this
work, we should wage the benefits and risks of xanthine treatment.
The main facts are as follows. (1) caffeine is the most widely
consumed and relatively safe psychoactive agent all over the world.
(2) Although treatment guidelines have regulated theophylline to
third-line treatment of bronchial asthma and chronic obstructive
pulmonary disease [136, 137], the rate of theophylline users among
asthmatic and COPD patients is relatively high [138]. (3) The antiinflammatory action of theophylline, observed in low dose, will
likely facilitate the worldwide use of theophylline again [117, 135].
(4) There is an intense, lengthy interdisciplinary endeavor for developing new, more selective and more effective xanthine derivatives. Although, according to large studies the moderate consumption of caffeine-containing beverages does not associate with an
increased cardiovascular mortality and morbidity, there are some
concerns that the use of methylxanthines should be taken into account in point of view of possible cardiovascular consequences.
Thus, it was emerged that methylxanthines are able to eliminate the
preconditioning actions of endogenous adenosine [139]. As adenosine receptors are highly implicated in ischemia/reperfusion process, the same suggestion might also be conceivable for treatment
with various xanthines having adenosine receptor-antagonist properties. As for the possible implication of theophylline and xanthine
structures, we will focus exclusively on four interesting aspects of
cardiac activity: possible implications for (1) preconditioning, (2)
postconditioning, (3) ischemia/reperfusion injuries, and (4) epigenetic processes in the heart.
4.1. Possible Implications for Preconditioning
It is widely believed that adenosine is a highly effective endogenous cardioprotective agent, which plays important role in
ischemic preconditioning. It has been observed that a short period
of ischemia increases the tolerance against a subsequent sustained
ischemia [140, 141]. This might be the basis of the experience that
the infarct size is smaller in patients who had several anginal attacks before acute myocardial infarction [140]. Preconditioning may
occur in two phases: an early phase, called also early preconditioning, and a delayed phase often mentioned as a second window of
protection. The delayed phase of ischemic preconditioning is supposed to implicate synthesis of cytoprotective proteins [142]. There
is good evidence that A1 and A3 adenosine receptors have crucial
role in adenosine-mediated preconditioning in both experimental
animals [143-149] and human subjects [150, 151]. In preconditiong,
the role of adenosine is supported by strong pharmacological evidence, indicating that various xanthine-type adenosine receptor
blockers, like 8-p-(sulphophenyl)theophylline, 8-(4-carboxyethenylphenyl)-1,3-dipropylxanthine (BW A1433), and 8-cyclopentyl1,3-dipropylxanthine (DPCPX) effectively eliminated preconditioning [147, 152]. Recently, Riksen et al. [139] and Meijer et al. [153]
have shown that acute caffeine administration prevented protection
in two different human models of ischemic preconditioning. Schae-
Current Medicinal Chemistry, 2011 Vol. 18, No. 24
3701
fer et al. [154], as well as Claeys and his associates [155] observed
that blockade of adenosine receptors with aminophylline limited
ischemic preconditiong in human beings. Tomai and his coworkers
[150] described that adenosine receptor blockade by bamiphylline
inhibited the ischemic preconditioning during coronary angioplasty.
The same group [156] has also demonstrated that bamiphylline
improved exercise-induced myocardial ischemia, increased the
ischemic threshold, prolonged exercise duration, delayed the onset
of anginal pain, and reduced the ST segment depression - possibly
via selective blockade of A1 adenosine receptors.
4.2. Possible Implications for Postconditioning
Myocardial ischemia is always followed by reperfusion associated myocardial necrosis and apoptosis. This reperfusion injury can
be diminished by postconditioning, which was first described by
Zhao et al. [157]. Postconditioning includes a brief ischemic episode immediately at the onset of reperfusion after a prolonged
ischemic episode. This intervention was shown to reduce the size of
the infarct area [157-159]. Although, the literature data are conflicting, it seems likely that A2A and A2B adenosine receptors may play
critical role in postconditioning [160-162], however, involvement of
A1 and A3 adenosine receptors have also been emerged [163].
4.3. Possible Implications for Ischemia/Reperfusion Injury
Adenosine is known to exert a protective effect against
ischemic injury. In the adenosinergic cardioprotection, practically,
all subtypes of adenosine receptors contribute. A1 adenosine receptor-induced cardioprotection operates when the receptors are activated prior to and during ischemia. During reperfusion, A1 adenosine receptor activation is not effective [163-167]. Although, in
human, the expression of A3 adenosine receptors is relatively poor,
there are pharmacological proofs to support the protective role of
A3 receptor activation both in the pre- and post-ischemic period, as
well as during ischemia [160, 168-170]. In contrast to A1 and A3
adenosine receptors, A2A and A2B adenosine receptors do not play a
significant role in the pre-ischemic and ischemic phase, but are
highly effective during reperfusion [163, 164, 170-173]. Several
experimental studies provide evidence that blockade of any of the
known adenosine receptor subtypes could somehow diminish the
cardioprotective action of adenosine [163, 174].
4.4. Possible Implications for Epigenetic Mechanisms
The term “epigenetics” describes all meiotically and mitotically
heritable alterations in gene expression that are not coded in the
DNA sequence itself [175]. Epigenetic mechanisms involves DNA
methylation, RNA-associated silencing and histone modification.
Histone modifications as epigenetic modifiers are post-translational
modifications of histones, including acetylation and methylation of
conserved lysine residues. Histone deacetylases (HDACs) regulate
cellular signaling and gene expression. Until recently, distinct genes
encoding 18 mammalian HDACs (grouped into Class I, II and III)
have been identified [176]. Histone deacetylase 2 (HDAC2) is a
critical factor for embryonic development and cytokine signaling
relevant for immune responses. Pathologic activity of this enzyme
can lead to various cardiac disturbances such as myocardial hypertrophy or heart failure [177]. Thus, inhibitors of HDAC2 enzyme
are considered as important cardiac drugs, to be applied e.g. for
prevention of myocardial hypertrophy [176, 178, 179]. It is noticeable that Class IIa HDACs (HDAC 4, 5 and 9) repress myocardial
hypertrophy and Class I and Class IIa enzymes have opposing roles
in regulation of cardiac myocyte growth and heart diseases [180].
The roles of various HDACs are quite complex and they might also
be involved in pathogenesis of cardiac arrhythmias and acute coronary syndromes [179].
This epigenetic mechanism might be significant in patients suffering from bronchial asthma and COPD. It was repeatedly de-
3702 Current Medicinal Chemistry, 2011 Vol. 18, No. 24
Szentmiklósi et al.
scribed that low concentrations of theophylline activated HDAC
and suppressed the activation of inflammatory genes [134, 181].
This action could be observed at low (1 to 10 M) theophylline
concentrations, whereas is lost at higher theophylline levels (100
M). Theophylline activates different subtypes of HDACs via an
intracellular site of action, but it appears that it has a relatively more
selective action on Class I than on Class II HDACs [182]. To our
best knowledge, there are no reports on the action of theophylline
and other xanthine derivatives on the cardiac HDACs, but it should
be strictly considered whether these low theophylline levels might
affect also the physiological or pathological cardiac functions? At
present, we do not know whether theophylline can be regarded as a
friend or a foe on the heart in this regard. Because the actions of
various HDACs are very complex, the outcome of activation of
these enzymes can be either beneficial or harmful. Extensive clinical studies are necessary to reveal the significance of this issue.
5. CONCLUSIONS
The main goal of this paper was to review the current state of
the medical use and perspectives of xanthine structures, such as
theophylline, caffeine and some of the novel adenosine subtypespecific xanthine derivatives. It can be stated that the conventional
methylxanthine theophylline is still frequently prescribed worldwide, but the frequency of adverse reactions and the relatively low
efficacy of this drug have led to reduced use in the pulmonological
practice. The recent recognition of the specific anti-inflammatory
action of low theophylline doses as a HDAC activator will possibly
significantly accelerate the worldwide application of theophylline.
It is tempting to speculate that the anti-inflammatory property of
theophylline or theophylline-derivatives could be used in not only
in bronchial asthma and COPD, but also in ischemia/reperfusion
injuries, such as heart transplantations or acute myocardial infarction. In the reperfusion phase of these cardiovascular events the
crucial role of the inflammatory processes are widely accepted
[183-186]. It has been shown that pretreatment with aminophylline
before coronary artery bypass grafting or heart transplantation improved the mechanical and biochemical functions of the heart in
human subjects [187, 188]. Regarding caffeine, this drug possibly
remains the most widely consumed psychoactive substance in the
future. There are intensive endeavors to synthesize new adenosine
subtype-selective xanthine derivatives. Two A1 subtype selective,
xanthine-type adenosine receptor antagonists were under clinical
trials (rolofylline, naxifylline), but these studies were discontinued.
At present, only toponafylline (BG-9928) is in a phase IIb clinical
O
H3C
It is surprising that relatively few subtype-selective xanthinetype antagonists were chosen for human studies and approximately
half of the trials were discontinued because of ineffectiveness or
adverse reactions. It appears that we should consider primarily the
cardiac actions of caffeine, theophylline and their derivatives. It
would be a useful option to develop compounds, like 8-p-(sulphophenyl)theophylline (8-SPT; Fig. 5), 8-(4’-carboxymethyloxyphenyl)-1,3-dipropylxanthine or 8-(4’-carboxymethyloxyphenyl)1,3-dipropylxanthine-2-aminoethylamide as theophylline derivatives, which are not able or very poorly able to penetrate the blood
brain barrier [189]. With the use of these types of compounds, the
central nervous system effects, like seizures, could effectively be
avoided.
The actual concern is that how xanthine structures could influence pre- and postconditioning, as well as ischemic-reperfusion
injuries. As highlighted above, there are clinical experiences indicating that methylxanthines can inhibit preconditioning and the
question emerged, whether these adenosine receptor antagonists can
blunt the cardioprotective activity of endogenous adenosines. First,
these clinical observations refer exclusively to acute administration
of methylxanthines. Until recently, there are no chronic human
trials. Second, there are experimental findings that adenosine receptors are upregulated and the adenosine-induced physiological responses are concomitantly increased under chronic exposure to
methylxanthines [79-83]. In this paper, we clearly demonstrated that
- at least in guinea pigs - the long-term administration of oral caffeine administration may strongly enhance the A1 adenosine receptor-induced electrical and mechanical responses in electrically
driven left atrial myocardium. These findings strongly suggest that
under chronic administration of caffeine or theophylline, adenosine
receptors participating in preconditioning or ischemia-reperfusion
processes are upregulated. Therefore, it can be predicted that longlasting exposures to these methylxanthines do not worsen, but
rather improve the effectiveness of these endogenous cardioprotective mechanisms. In addition, it should be taken into account that
caffeine is capable of inducing a dose-related increase of plasma
adenosine levels [190]. These factors together could likely ensure
the integrity of endogenous cardioprotective mechanisms. At any
rate, in the light of a number of large prospective studies it can be
CH3
H3C
CH3
N
F
O
N
N
O
trial for treating heart failure (Fig. 4). Xanthine-type A2A antagonists were also under clinical trial in Parkinson disease, e.g. istradefylline (KW-6002) and ST-1535. ST-1535 is under phase I trial,
whereas the study with istradefylline was discontinued [130]. Two
xanthine-type A2B adenosine receptor antagonists are under clinical
development for bronchial asthma (ATL 844 and GS 6201) [130].
N
H
N
N
O
CH3
O
N
N
O
CH3
CH3
Istradefylline (KW-6002)
GS 6201 (CVT-6883)
O
H3C
O
H
N
N
O
S
N
N
CH3
8-p-(sulphophenyl)theophylline
Fig. (5). Chemical structures of istradefylline, GS 6201, and 8-SPT.
O
OH
F
N
N
F
Xanthine Derivatives in the Heart
ascertained that chronic, but moderate coffee consumption (which
is the main source of caffeine intake) does not increase generally
the risk of coronary disease and heart failure. There might be, of
course, adverse reactions associated mainly to the cardiac and neurohumoral actions of acute caffeine exposition, but these reactions
might occur in a specific vulnerable population, in elderly and hypertensive patients, or when the possible adverse reactions are genetically determined [4, 191, 192]. The extremely high coffee consumption, however, carries large cardiovascular risk.
In conclusion, at present we are in a position to apply rational
drug design also in the platform of adenosinergic pharmacology as
there is a progressively accumulating knowledge both on the beneficial and harmful actions of endogenous and exogenous adenosine.
The main goal is the development of novel structures that mimic the
actions of the conventional methylxanthines as lead compounds, but
their adenosine receptor subtype-specificity are higher, their water
solubility are optimal, and the frequency of their adverse reactions
are minimal. Therefore, the search for potent and subtype-selective
adenosine receptor antagonists has been one of the most highly
studied areas in medicinal chemistry [130, 193-198]. An attractive
approach of drug development could be to synthetize pharmacologically silent, clinically viable, site- and event-specific allosteric
adenosine receptor antagonists with subtype selectivity, which
could be an enormous challenge for both academic and industrial
research groups.
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Received: April 13, 2011
Revised: July 08, 2011
Accepted: July 10, 2011
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