Caffeine actions

C7H9N402- M.p. 337 C, an alkaloid obtained from cacao seeds or prepared synthetically. Constitutionally it is similar to caffeine, and is also a weak base. It is usually administered as the sodium compound combined with either sodium ethanoate or sodium salicylate, and is employed almost entirely as a diuretic. Physiologically theobromine resembles caffeine, but its effect on the central nervous system is less, while its action on the kidneys, is more pronounced. 

Caffeine (128) and dimethyl sulfate in nitrobenzene give the fully methylated dioxo compound 129. In the same way that 2,4-dialk-oxypyrimidines give unstable quaternary salts which decompose to the N-alkyl oxo compounds even at room temperature, the action of... 

Contraction is a general term that refers to the mechanically activated state of myofibrils which is usually caused by action potentials). Contracture means muscle shortening or tension development, which is not triggered by action potentials), e.g. K+ contracture, and caffeine or halothane contracture. The word is also used for deformity or distortion of fingers, hand or limb, such as Dupuytren s or Volkmann s contracture. 

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. 

Caffeine is a mild to potent CNS stimulant, with the degree of its stimulating effect dependent on the dose administered. Caffeine stimulates the CNS at all levels, including the cerebral cortex, die medulla, and the spinal cord. Caffeine has mild analeptic (respiratory stimulating) activity. Other actions include cardiac stimulation (which may produce tachycardia), dilatation of coronary and peripheral blood vessels, constriction of cerebral blood vessels, and skeletal muscle stimulation. Caffeine also has mild diuretic activity. 

Ryanodine, another plant alkaloid, can also open SR channels and thereby induce contraction. Ryanodine differs from caffeine in that it seems to have a larger effect on the closure rate constants than on opening rate constants. Thus it is often said in the literature that caffeine can open channels but ryanodine merely keeps them open. The actions of caffeine and ryanodine are mutually competitive (occlusive). However, they are experimentally completely independent of the effects of IP3. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

How would you describe the differences between a cup of coffee and a cup of hot water What probably come to mind are the aroma, the dark color, and the taste of a good cup of coffee. Coffee s action as a stimulant is another obvious difference. These properties come from the chemical compounds that hot water dissolves from ground coffee beans. These compounds are molecules constructed from different atoms bound together in veiy specific arrangements. The molecule that makes coffee a stimulant is caffeine. Our background photo is a magnification of crystals of pure caffeine, and the inset is a ball-and-stick model of this molecule. 

KAJiMOTO G (1963) On the antioxidative components and antiseptic components in tea. Part 111. The synergistic action of caffeine to catechin components , Nihon Shokuhin... 

Schardt D, Schmidt S. Caffeine The Inside Scoop. Nutrition Action Health Letter. Vol 23 (10) December 1996. Center for Science in the Public Interest, Washington, D.C. 

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. 

Daly, J. W., Mechanism of action of caffeine, in Caffeine, Coffee, and Health, Garattini, S., Ed., Raven Press, New York, 1993, 97. 

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... 

Nehlig, A., Daval, J. L., and Debry, G., Caffeine and the central nervous system Mechanisms of action, biochemical, metabolic, and psychostimulant effects, Brain Research Reviews, 17, 139, 1992. 

Hasenfratz, M., and Battig, K., Action profiles of smoking and caffeine Stroop effect, EEG, and peripheral physiology. Pharmacology, -Biochemistry-and-Behavior 42(1), 155-161, 1992. 

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. 

Fredholm, B. B., Battig, K., Holmen, J., Nehlig, A. Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 51, 83-133. 

Some CNS stimulants have an effect on the same systems that are involved in wakefulness, including glutamate-, NE-, DA-, 5-HT-, histamine-, hypocretin- and ACh-containing neurons. This group includes molecules such as cocaine, amphetamine, and nicotine. The sleep-promoting systems are concentrated in the medial part of the brainstem, dorsal reticular substance of the medulla, anterior hypothalamus, and basal forebrain (Jones 2005). Other stimulants, such as caffeine and theophylline, block some sleep-inducing mechanisms. Modafinil is also a CNS stimulant with an unknown mechanism of action. 

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. 

Caffeine (10 mM), an agonist for CICR, is unable to produce any rise of Ca2+ or force in myometrium (Taggart Wray 1998, Kupittayanant et al 2001a). These data are also in agreement with earlier force measurements reporting no rise in force (Savineau Mironneau 1990) indeed caffeine relaxes the uterus, due to its inhibitory action on the phosphodiesterase that breaks down cAMP (Arnaudeau et al 1994a). 

Savineau JP, Mironneau J 1990 Caffeine acting on pregnant rat myometrium analysis of its relaxant action and its failure to release Ca2+ from intracellular stores. Br J Pharmacol 99 261-266... 

Burdyga Yes. In the guinea-pig ureter application of caffeine (1—2 mM) increases the frequency of Ca2+ sparks and STOCs, and under current-clamp conditions this causes a decrease of the plateau component of the action potential, thus bringing down the Ca2+ and force. In contrast, CPA inhibits Ca2+ sparks and STOCs, and increases the duration of the plateau component of the action potential. This results in an increase in the duration of the Ca2+ transient and amplitude and duration of the phasic contraction. 

Burdyga That s my feeling. I can clearly see that when I apply caffeine it induces Ca2+ sparks and Ca2+ waves. If I stimulate the cells using high-K+ solution to initiate action potential I can see that Ca2+ transient rises instantly in all parts of the cell. In most cases the amplitude of Ca2+ signal is smaller and the kinetics of the Ca2+ rise is slower in the area of the major initiating site, and CPA eliminates the difference, so it must be acting as a buffer. 

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