From the FDA Drug Label
Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP) This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation.
Decreased cAMP means less relaxation of muscle contraction, which implies more muscle contraction. This is because the increase in cAMP leads to relaxation, so a decrease would have the opposite effect 1.
- Key points:
- Increased cAMP leads to relaxation
- Decreased cAMP leads to less relaxation, implying more muscle contraction
- This relationship is based on the effect of cAMP on airway smooth muscle contraction 1
From the Research
Decreased cAMP generally leads to increased muscle contraction, as it reduces the activity of protein kinase A (PKA), allowing myosin light chain kinase (MLCK) to become more active and promote contractile force. This mechanism is supported by a study published in 2016 2, which found that cAMP inhibits Ca(2+) sensitization in human detrusor smooth muscle contraction, and that the PKA-dependent pathway is dominant in this process.
When cAMP levels fall in smooth muscle cells, it reduces the activity of PKA, which normally phosphorylates and inhibits MLCK. With less PKA activity, MLCK becomes more active and phosphorylates myosin light chains, enabling them to interact with actin filaments and generate contractile force. Additionally, decreased cAMP allows calcium levels to rise within muscle cells, further promoting contraction.
This mechanism is particularly important in smooth muscle, where hormones and neurotransmitters that decrease cAMP (such as norepinephrine acting on alpha-adrenergic receptors) cause vasoconstriction. Conversely, medications that increase cAMP levels, like beta-2 agonists (albuterol) or phosphodiesterase inhibitors (theophylline), promote muscle relaxation and are used to treat conditions like asthma and COPD by relaxing bronchial smooth muscle.
Some studies have investigated the role of cAMP in muscle contraction, including a study published in 2022 3, which found that pyridostigmine, a medication used to treat myasthenia gravis, has a median effectiveness of 60 and a net benefit of 65, but is also associated with side effects such as flatulence, urinary urgency, and muscle cramps. However, the most recent and highest quality study on this topic is the 2016 study published in BJU International 2, which provides the most relevant evidence for the relationship between cAMP and muscle contraction.
Key points to consider include:
- Decreased cAMP leads to increased muscle contraction
- PKA-dependent pathway is dominant in smooth muscle contraction
- Medications that increase cAMP levels promote muscle relaxation
- cAMP inhibits Ca(2+) sensitization in human detrusor smooth muscle contraction
- Side effects of medications that affect cAMP levels, such as pyridostigmine, should be considered in clinical practice.