What are the basic cellular actions of caffeine?

Updated: Jun 14, 2018
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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The diverse effects of methylxanthines are probably attributable to the following 3 basic cellular actions, listed in order of increasing importance:

  • Translocations of intracellular calcium

  • Increasing accumulation of cyclic nucleotides

  • Adenosine receptor blockade

The ability of methylxanthines to inhibit cyclic nucleotide phosphodiesterases is often cited to explain their therapeutic effects; however, strong evidence for this theory is lacking. Plasma caffeine concentrations that raise blood pressure are below the threshold for phosphodiesterase inhibition. Thus, phosphodiesterase inhibition is probably not important to the therapeutic effects of methylxanthines.

At high concentrations (0.5-1 mmol/L), caffeine interferes with the uptake and storage of calcium by the sarcoplasmic reticulum in striated muscles. This action can account for the observations that such concentrations of caffeine increase the strength and duration of contractions in both skeletal and cardiac muscles. Similar actions can enhance secretion in certain tissues. However, they are unlikely to play an important role at therapeutic concentrations.

In vitro, methylxanthines (at concentrations of approximately 0.2 mmol/L or higher) generally cause relaxation of vascular smooth muscles in the presence of various stimulators of contraction (eg, norepinephrine and angiotensin). Although this relaxation probably results from a reduction of the cytosolic calcium concentration, it is unclear to what extent methylxanthines can alter calcium binding and transport, either directly or indirectly, by altering cyclic nucleotide metabolism.

Thus, adenosine receptor blockade appears to be the predominant mode of action. Methylxanthines act as competitive antagonists at adenosine receptors at concentrations well within the therapeutic range. The effects of exogenous adenosine frequently oppose those of methylxanthines, and in some experimental settings, removing ambient adenosine (by adding adenosine deaminase) can reproduce the actions of methylxanthines. Plasma concentrations of caffeine that raise blood pressure are within the range for antagonism of adenosine receptors.

Several other caffeine actions that have received relatively little attention to date might prove to be important for certain methylxanthine effects. These include their potentiation of inhibitors of prostaglandin synthesis and the possibility that methylxanthines reduce the uptake or metabolism of catecholamines in nonneuronal tissues.

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