Xanthine Derivatives in the Heart: Blessed or Cursed?

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 (A(1), A(2A), A(2B) and A(3)) 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.

Theobromine and related methylxanthines as inhibitors of Primary Amine Oxidase

“…Likewise, substitutions on the nitrogen atom at position 1 of theobromine give rise to the anti-inflammatory lisofylline and the antihistamine pentoxifylline (Pascal, Beranger, Pinhas, Poizot, & Désiles, 1985). Di-substituted derivatives, such as the 3, 8 substituted compounds bamiphylline, naxifylline, and rolofylline, with increased solubility, have also been investigated as cardioprotective drugs (Szentmiklósi et al, 2011). The effects of many of these drugs on MAO and PrAO have not been assessed although there is evidence that the inhibition of both enzymes may be beneficial in the management of neurodegenerative diseases, in combatting oxidative stress (Liu, Wu, Lu, Lai, & Hou, 2010) and in the treatment of obesity (Carpéné, Iffiú-Soltesz, Bour, Prévot, & Valet, 2007).…”

Uric acid as one of the important factors in multifactorial disorders – facts and controversies

“…The effects of allopurinol action as a xanthine-oxidase inhibitor are increasing of intermediates, hypoxanthine and xanthine, and decreasing of final product uric-acid (33). Taking into account that xanthine derivatives are widely used medicaments in treatment of different disease (inflammatory diseases, behavioral, neurodegenerative diseases, renal diseases, respiratory diseases, cancer pain etc, (34) the effect of xanthine or hypoxhantine should be considered in explanations of the mechanisms involved in effects of XOR inhibition (35). It is well known that widely used and examinated xanthine derivative is caffeine.…”

Zebrafish Embryo as an In Vivo Model for Behavioral and Pharmacological Characterization of Methylxanthine Drugs

“…Caffeine is used as an analeptic and central nervous system stimulant and it is also the most widely consumed psychoactive agent [8]. Theobromine is mainly found in cacao and recent evidence shows that it has great potential as an antitussive agent [9].…”

“…Theobromine is mainly found in cacao and recent evidence shows that it has great potential as an antitussive agent [9]. Theophylline, aminophylline, doxofylline and diprophylline are used in the therapy of bronchial asthma and chronic obstructive pulmonary diseases (COPD) [8,10,11,12,13]. In particular, doxofylline and diprophylline are two novofyllines synthesized to have fewer side effects than other methylxanthines [11,12,13].…”

“…In particular, doxofylline and diprophylline are two novofyllines synthesized to have fewer side effects than other methylxanthines [11,12,13]. Pentoxifylline is used in the treatment of peripheral vascular diseases and in the management of cerebrovascular insufficiency and diabetic nephropathy [8,10]. Etofylline, another synthetic derivative, is used in lowering the blood lipid level [14].…”