MadSci Network: Cell Biology

Re: How and why does caffine effect the pulse rate of a person

Date: Thu Feb 10 16:59:13 2000
Posted By: Michael Onken, Post-Doc, Wash U
Area of science: Cell Biology
ID: 949437237.Cb

The short answer is that caffeine increases pulse rate because caffeine increases the strength and frequency of heartbeats. Since that doesn't really tell you any more than you already knew, I'll give you the long answer, which, unfortunately, requires a lot of cell biology and biochemistry to fully explain.

Caffeine is a methylxanthine (1,3,7-trimethylxanthine to be exact), which is a modified purine. Since adenine and guanine are also purines, methylxanthines can act as inhibitors of enzymes that use compounds containing adenine or guanine as substrates. A prime example of this is an enzyme called 3,5- cyclic nucleotide phosphodiesterase (cAMP-PDE) that converts cyclic Adenosine Monophosphate (cAMP) into non-cyclic Adenosine Monophosphate (AMP). When caffeine or another methylxanthine is applied to a cell, it inhibits the activity of cAMP-PDE by binding to the site of the enzyme that usually binds the adenine of cAMP, such that cAMP-PDE can no longer convert cAMP to AMP. This may seem like boring biochemistry, and it is, so let's pull back to the whole cell and see what the effect is.

As you probably already know, a cell's activity is often regulated by various hormones. One of the ways that hormones can effect a cell's activity is by binding to specific hormone receptors that activate G-proteins, which then go on to activate other enzymes that direct the cell to function. One such hormone that activates G-proteins is epinephrine (Adrenalin). When epinephrine binds the ß- adrenergic receptor ("adrenergic" means "adrenalin activated"), this activates a G-protein that in turn activates an enzyme called adenylate cyclase that converts ATP (adenylate) into cAMP. The cAMP produced by adenylate cyclase then diffuses through the cell and acts as a "secondary messenger": activating various enzymes including Protein Kinase A (PKA; cAMP- dependent Protein Kinase), which in turn activates enzymes involved in metabolism as well as in other signalling pathways.

This latter affect of PKA is especially important in the heart, where increased PKA activity increases the responsiveness of heart muscle cells (cardiomyocytes) to the Calcium currents that control beating. PKA does this by adding phosphate molecules ("phosphorylating") several proteins that regulate heart functions, like membrane channels and contractile proteins, as well as activating various genes by phosphorylating transcription factors, like C/EBP.

So the net reaction, as pictured here, is: epinephrine binding results in increased cAMP levels which affects several cellular processes by activating PKA. As mentioned above, caffeine inhibits cAMP-PDE. The result being that any cAMP generated by adenylate cyclase will remain active in the cell for longer than usual. This isn't a problem for most cells, since hormone binding is still required to activate adenylate cyclase. However, many cell types, including heart muscle cells, are "high-cycling" regarding cAMP regulation. This means that in these cells, the activities of adenylate cyclase and cAMP-PDE are both maintained at very high levels, so that even a minor change in the activities of either enzymes creates a relevant shift in cAMP levels. This makes the cells much more responsive to hormones (which is the reason for being "high-cycling"), but also much more responsive to caffeine. So, by slowing down cAMP-PDE activity in "high- cycling" cells, caffeine increases the levels of cAMP in those cells, mimicking the effects of epinephrine.

Before ending, I should include another related mechanism of caffeine's effect on cAMP levels. Beside cAMP-PDE, caffeine (and other methylxanthines) can inhibit the activity of the A1 Adenosine Receptor, a receptor in the membranes of some cells which binds to adenosine (adenine + ribose). The job of this receptor is to inhibit adenylate cyclase when it binds adenosine. The A1 receptor is specifically found in certain nerve cells (for instance, innervating the heart) and uses adenosine as a counter-balance to adenylate cyclase-activating hormones. By inhibiting this adenosine receptor, caffeine removes this check, such that adenylate cyclase activity becomes even more sensitive to hormone binding. Thus, by preventing various enzymes from binding to molecules containing adenine, caffeine can yield the same physiological effects as epinephrine, though less intense. Finally, over time, cells alter their enzyme levels to compensate for the higher cAMP levels resulting from caffeine usage. This means that, over time, the effects of caffeine on the system lessen, such that more caffeine is required to produce the same effect, and complete withdrawal from caffeine after continuous usage can result in headaches and lethargy as the cells try to reset their machinery.

May 1, 2002
Julien from International High School adds:

Another site, in an article written by Marshall Brain, says that the blockage of the adenosine receptors results in the pituitary gland's stimulating the adrenal glands to release adrenaline into your body. The way I interpreted the articles was that the blockage of adenosine receptors in the brain causes the secretion of adrenaline in the body which in itself increases the heart rate but in addition the cAMP levels remain higher due to the inhibition of cAMP-PDE by caffeine and so the heart rate is increased by both phenomena.

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