Introduction to Adenosine and Tachycardia

By SWA

  • What is Adenosine?
    • Adenosine is a chemical found in human cells, existing in three forms: adenosine, adenosine monophosphate (AMP), and adenosine triphosphate (ATP).
    • Adenosine is a chemical found in the body that plays many roles, including influencing heart rate and promoting sleep and relaxation. It is also used as a medication to manage certain types of tachycardia, particularly supraventricular tachycardia. Adenosine works by slowing the heart rate through its action on the cardiac tissue.

    • Adenosine production in the body occurs through multiple pathways:

    • Phosphorylation of Adenine: Adenine can be directly phosphorylated to form AMP (adenosine monophosphate), which is then converted to ATP, ADP, and finally adenosine through dephosphorylation reactions.

    • Breakdown of ATP: Adenosine is primarily formed in the body through the breakdown of ATP, which releases energy. ATP can be dephosphorylated stepwise through the action of various enzymes:

      • ATP is first converted to ADP (adenosine diphosphate), and then to AMP.
      • AMP is further dephosphorylated by the enzyme 5'-nucleotidase to form adenosine.

    • S-Adenosyl Methionine (SAM) Decomposition: SAM serves as a methyl donor in numerous methylation reactions and is eventually transformed into S-Adenosyl Homocysteine (SAH), which is then hydrolyzed to adenosine and homocysteine.

    • Salvage Pathways: Adenosine can also be recycled from other adenosine compounds. Cells can salvage adenosine from the breakdown products of RNA and DNA through various salvage pathways.

    • Adenosine accumulation in the brain throughout the day is primarily a byproduct of neuronal activity and ATP metabolism. 

The Role of Adenosine in the Body

  • Function in Sleep
    • During sleep, the brain metabolizes the excess adenosine accumulated throughout the day, highlighting one of the major restorative functions of sleep.
  • Impact on Wakefulness and Sleepiness
    • As wakefulness prolongs, adenosine levels gradually increase in brain areas important for arousal, like the reticular activating system in the brainstem. Higher concentrations of adenosine inhibit arousal, leading to sleepiness.
  • Clearance During Sleep
    • Adenosine is cleared from the brain during sleep, demonstrating the body's natural mechanism for managing adenosine levels.

Adenosine in Medical Treatment

  • Treating Supraventricular Tachycardia
    • Adenosine is used to treat supraventricular tachycardia by producing a transient atrioventricular nodal block when administered as an intravenous bolus. This is beneficial for converting the majority of paroxysmal supraventricular tachycardias to sinus rhythm.

Imbalances in Adenosine Levels

  • Excessive Adenosine Production
    • Chronic overproduction of adenosine can lead to pathological states, contributing to chronic inflammation, fibrosis, and organ damage.
  • Symptoms of Too Little Adenosine
    • Adenosine deaminase-deficient severe combined immunodeficiency, usually presenting before 6 months of age, is characterized by serious lung infections, chronic diarrhea, skin rashes, and slow growth. Symptoms beginning later in life tend to be milder.

    Supraventricular tachycardia (SVT), a group of rapid heart rate conditions.

    List of some of the more common and less common symptoms associated with adenosine

    Common Symptoms

  • Flushing: A warm, red feeling typically on the face.
  • Sense of impending doom: A temporary feeling of extreme dread.
  • Chest pain or discomfort: This can range from mild to severe.
  • Shortness of breath or difficulty breathing: This is usually transient.
  • Heart palpitations: Feeling like the heart is fluttering, pounding, or skipping beats.
  • Lightheadedness or dizziness: Due to changes in heart rhythm or blood pressure.

Less Common Symptoms

  • Nausea: Feeling sick to the stomach.
  • Headache: This can vary from mild to severe.
  • Sweating: Excessive perspiration not related to physical exertion.
  • Tightness in the throat: A feeling of constriction in the throat area.
  • Metallic taste: An unusual taste in the mouth, often described as metallic.

Rare Symptoms

  • Hypotension: Abnormally low blood pressure, which can lead to dizziness or fainting.
  • Bronchospasm: Constriction of the airways in the lungs, leading to difficulty breathing, especially in individuals with asthma.
  • Seizures: Very rare, but seizures have been reported in some cases.

Transient Effects

Most of the symptoms associated with adenosine administration are transient and last only a few seconds to minutes, as adenosine has a very short half-life. The body quickly metabolizes the drug, leading to the rapid cessation of symptoms.

1. ATP Metabolism

  • Energy Use: Adenosine triphosphate (ATP) is the primary energy currency in cells, including neurons. As cells perform various functions, they consume ATP, breaking it down into adenosine diphosphate (ADP), adenosine monophosphate (AMP), and eventually adenosine.
  • Breakdown Process: The breakdown of ATP to ADP and further to AMP and adenosine occurs through enzymatic reactions. This process is a part of normal cellular metabolism and increases with heightened neuronal activity.

2. Neuronal Activity

  • Increased Activity: Throughout the day, especially during periods of wakefulness and mental exertion, neurons in the brain are highly active. This activity requires substantial energy, leading to an increased breakdown of ATP.
  • Release of Adenosine: As neurons fire and use up ATP, the resulting increase in adenosine levels in the extracellular space of the brain acts as a feedback mechanism. Adenosine then influences various receptors to modulate neuronal activity, potentially leading to reduced neuronal firing over time.

3. Role of Adenosine

  • Feedback Mechanism: Adenosine acts as a neuromodulator in the brain. It binds to adenosine receptors, leading to a variety of effects, including vasodilation and the modulation of neurotransmitter release.
  • Promotion of Sleepiness: One significant effect of increased adenosine levels is the promotion of sleepiness. Adenosine accumulates during wakefulness, binding to specific receptors (such as the A1 and A2A receptors) that play a key role in sleep regulation. This accumulation is thought to contribute to the drive for sleep, as part of the homeostatic regulation of sleep-wake cycles.

Conclusion

Adenosine plays a crucial role in various bodily functions, from regulating sleep and wakefulness to treating specific heart conditions. However, maintaining balanced adenosine levels is vital, as both deficiencies and excesses can lead to health issues.

The cycle of adenosine accumulation during wakefulness and its clearance during sleep highlights the complex interplay between cellular energy metabolism and the regulation of sleep-wake cycles. Adenosine serves as a crucial neuromodulator, signaling the need for rest through its accumulation and contributing to the restorative power of sleep by its clearance. Understanding this cycle not only sheds light on the importance of sleep for health but also underscores the potential impacts of adenosine imbalances on the body.

Reference: 

Molecular Therapy. "adeno-associated virus (AAV)"
Ex vivo and in vivo suppression of SARS-CoV-2 with combinatorial AAV/RNAi expression vectors: https://www.sciencedirect.com/science/article/pii/S1525001622000247

Adenosine https://www.youtube.com/watch?v=2WN0batGgPc


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