Caffeine Adenosine

The methylxanthine molecule is built on a foundation common to many biologic compounds, the xanthine double ring of carbons. The three methylxanthines, caffeine, theophylline, and theobromine, all block the action of the body s adenosine molecule, sending a signal that helps slow the chemical buildup inside cells. Because the methylxanthines closely resemble adenosine at the molecular level, they can occupy the molecular sites on cells that normally recognize, and react to, adenosine. Caffeine prevents the normal slowing action of adenosine at the cellular level, in both nerves and muscle. 

Adverse effects with dipyridamole thallium testing are minimal, the main adverse effects being chest pain (with or without ischemic changes on the ECG), headache, dizziness, and nausea. Adverse effects are related to the increased adenosine activity and can be ameliorated by xanthine compounds because they are direct competitive antagonists of adenosine. Caffeine products must be avoided for about 24 hours prior to the test. Adenosine is associated with a higher incidence of adverse effects (80% versus 50%), but these are very transient, and some studies have shown that patients prefer it over dipyridamole. Both agents are relatively contraindicated in patients with a history of bronchospasm. 

In addition, adenosine is implicated in sleep regulation. During periods of extended wakefulness, extracellular adenosine levels rise as a result of metabolic activity in the brain, and this increase promotes sleepiness. During sleep, adenosine levels fall. Caffeine promotes wakefulness by blocking the interaction of extracellular adenosine with its neuronal receptors. ... 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Beyond Viagra, there are a number of other PDE inhibitors that are used clinically. In fact, the classic drugs papaverine and dipyridamole were used clinically before their effects on PDEs were known. Caffeine and theophylline (a compound found in tea) are also PDE inhibitors. However, all of these drugs most likely have multiple targets, making conclusions regarding the roles of PDEs in processes that are sensitive to these agents difficult to interpret. Certainly, some of their effects are due to their actions on adenosine receptors. 

It is added to pain relievers because it enhances the effects of aspirin and because many headaches are caused by caffeine withdrawal. Caffeine closes down blood vessels by competing with adenosine, and helps alleviate the vascular headaches caused by withdrawal. 

Caffeine binds to adenosine receptors in the brain, preventing adenosine from inducing sleep or opening blood vessels. Caffeine also increases levels of dopamine, the neurotransmitter associated with pleasure. This is the chemical mechanism for addiction. The response to adenosine competition causes increased adrenaline flow. 

The properties of a particular molecule are due to the types and number of atoms it contains and how those atoms are arranged in space. Caffeine is a stimulant because it has the same shape as one part of cyclic adenosine monophosphate (cyclic AMP), a molecule that helps to regulate the supply of energy in the brain. When caffeine is absorbed into the blood and carried to the brain, it binds to an enzyme that normally controls the supply of cyclic AMP. As a result, the enzyme can no longer bind cyclic AMP, the brain s supply of this energy-regulating molecule is increased, and we feel stimulated. 

The body responds to chronic presence of caffeine by increasing the number of adenosine receptor sites. This may be one of the reasons for the increased tolerance (and decreased efficacy as a stimulant) to caffeine in heavy coffee and tea drinkers. 

Caffeine and theophylline affect cerebral circulation, most likely through their effect as adenosine antagonists. 

The often severe headaches, common in caffeine withdrawal, appear to be caused by vasodilation of cerebral blood vessels. This action is probably mediated by the action of the methylxanthines on adenosine receptors. 

Three major mechanisms of action have dominated as possible explanations for the ergogenic potential of caffeine in the enhancement of exercise performance. These three mechanisms involve (1) the mobilization of intracellular calcium from the sarcoplasmic reticulum of skeletal muscle, (2) the increase of cyclic-3 ,5 -adenosine monophosphate (cAMP) by the inhibition of phosphodiesterases in muscles and adipocytes, and (3) the competitive antagonism of adenosine receptors, primarily in the central nervous system (CNS).8 9... 

The most promising mechanism of action, which may account for some of caffeine s potential ergogenic effects, involves its demonstrated ability as a competitive antagonist of the depressant effects of adenosine analogs in the central nervous system. Adenosine and its derivatives have been shown to inhibit neuronal electrical activity, the release of neurotransmitters, and to interfere with synaptic transmission.19-24 27... 

Caffeine is also effective in the antagonism of peripheral adenosine (type I) receptors, which are known to inhibit lipolysis by subduing adenylate cyclase activity.28 The appeal of this mechanism of action is that the majority of the pharmacological effects of adenosine on the central nervous system can be inhibited by doses of caffeine that are well within physiologically non-toxic levels comparable to only a couple of cups of coffee.5... 

Snyder, S. H., Adenosine as a mediator of the behavioral effects of xanthines, in Caffeine Perspective from Recent Research, Dews, P. B., Ed., Springer Verlag, Berlin, 1984, chap. 3. 

Zhang, Y. and Wells, J., The effects of chronic caffeine administration on peripheral adenosine receptors, Journal of Pharmacology and Experimental Therapeutics, 254, 757, 1990. 

The main mechanism of action of caffeine occurs via the blockade of adenosine receptors in the CNS. Adenosine is an autacoid, which is involved in the modulation of behavior, oxygenation of cells, and dilatation of cerebral and coronary blood vessels and indirectly inhibits the release of dopamine. The blockade of adenosine receptors by caffeine increases the activity of dopamine, which is implicated in the effects of caffeine (91). The question that arises from this observation is to know whether or not adenosine antagonists hold potential for the treatment of Parkinsonism, and further study on the adenosine receptor antagonists from medicinal plants should be encouraged. A possible source for such agents could be the medicinal flora of Asia and the Pacific, among which is the family Sapindaceae. 

Kuzmin, A., Johansson, B., Gimenez, L., Ogren, S. O. Fredholm, B. B. (2005). Combination of adenosine A(l) and A(2A) receptor blocking agents induces caffeine-like locomotor stimulation in mice. Eur. Neuropsychopharmacol. 00, 000-000. 

Virus, R. M., Ticho, S., Pilditch, M. Radulovacki, M. (1990). A comparison of the effects of caffeine, 8-cyclopentyltheophylline, and alloxazine on sleep in rats. Possible roles of central nervous system adenosine receptors. Neuropsychopharmacology 3 (4), 243-9. 

The importance of adenosine deaminase in the duration and intensity of sleep in humans has been noted recently (Retey et al. 2005). Animal studies suggest that sleep needs are genetically controlled, and this also seems to apply in humans. Probably, a genetic variant of adenosine deaminase, which is associated with the reduced metabolism of adenosine to inosine, specifically enhances deep sleep and slow wave activity during sleep. Thus low activity of the catabolic enzyme for adenosine results in elevated adenosine, and deep sleep. In contrast, insomnia patients could have a distinct polymorphism of more active adenosine deaminase resulting in less adenosine accumulation, insomnia, and a low threshold for anxiety. This could also explain interindividual differences in anxiety symptoms after caffeine intake in healthy volunteers. This could affect the EEG during sleep and wakefulness in a non-state-specific manner. 

Although caffeine is known to mobilize intracellular calcium, to inhibit phosphodiesterase activity, and to increase in vitro 5-HT and NE concentrations in the brainstem (Garrett and Griffiths 1997 Berkowitz et al. 1970 Carter et al. 1995 Solinas et al. 2002), it is now widely accepted that the mechanism of action of caffeine on wakefulness, at least at the dose range produced by voluntary caffeine intake, is via the antagonism of adenosine receptors. 

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