Nifedipine's Effects on Cell Motility and Cellular Functions
Nifedipine interferes with cellular functions by inhibiting iron uptake into cardiac cells through L-type calcium channels and can directly affect neurotransmitter release independently of its calcium channel blocking action. 1
Mechanisms of Nifedipine's Effects on Cellular Functions
Iron Transport Inhibition
Nifedipine has been shown to affect cellular functions through multiple mechanisms:
Cardiac Iron Uptake: Research indicates that nifedipine hinders iron uptake into cardiac cells by blocking L-type calcium channels (LTCC), which serve as a pathway for iron entry 1
- L-type calcium channels can transport not only calcium but also other divalent ions such as Fe²⁺
- This effect is being explored in a pilot study in humans for potential therapeutic applications in iron overload conditions
Cell Motility Impact: By interfering with calcium-dependent processes, nifedipine can affect cell motility, as calcium signaling is crucial for cytoskeletal reorganization and contractile functions in various cell types
Neurotransmitter Release Effects
Nifedipine has cellular effects beyond calcium channel blockade:
Direct Effect on Neurotransmitter Release: Nifedipine causes long-lasting facilitation of tetrodotoxin-insensitive spontaneous glutamate release, independent of its L-type calcium channel blocking effect 2
- This effect is dose-dependent with an EC₅₀ of 7.8 μM
- Even at clinically relevant doses as low as 100 nM, nifedipine can increase neurotransmitter release
- At 10 μM concentration, neurotransmitter release increases 14.7-fold
Calcium-Independent Mechanism: This effect on neurotransmitter release is largely calcium-independent, as it is not inhibited by Cd²⁺, thapsigargin, or BAPTA-AM 2
- Nifedipine appears to act on the release process downstream of calcium entry or release
- This effect is not mediated by protein kinases A or C
Intracellular Calcium Regulation
Nifedipine affects intracellular calcium levels:
- Reduction of Intracellular Calcium: In primary hyperparathyroidism, nifedipine reduces elevated intracellular calcium levels 3
- This suggests nifedipine affects calcium homeostasis beyond simple channel blockade
Clinical Implications
Iron Overload Cardiomyopathy
Nifedipine's ability to block iron uptake has potential therapeutic applications:
- Prevention of Iron Accumulation: Studies in mice showed that calcium channel blockers inhibited LTCC current in cardiac myocytes, attenuating myocardial iron accumulation and oxidative stress 1
- This led to improved survival, prevented hypotension, and preserved heart structure and function
- A clinical trial sponsored by the National Institute of Diabetes and Kidney Disease is evaluating nifedipine's role in iron overload patients
Adenosine Interactions
Nifedipine has effects beyond calcium channel blockade:
- Adenosine Potentiation: Nifedipine inhibits adenosine uptake from and release into the extracellular space and binds at adenosine receptors 4
- This interaction may explain some of nifedipine's side effects that are similar to adenosine effects
Limitations and Considerations
Specificity Among Calcium Channel Blockers: The effect on iron uptake appears to be specific to nifedipine and is not mimicked by other dihydropyridines such as nimodipine or nicardipine 2
Potential Side Effects: Nifedipine's action as a secretagogue directly targeting the release process may explain some of its side effects 2
Clinical Relevance: The cellular effects of nifedipine occur at concentrations that are clinically achievable, suggesting these mechanisms may be relevant in patients receiving the drug 2, 5
In conclusion, nifedipine has multiple effects on cellular functions beyond its well-known calcium channel blocking properties, including inhibition of iron uptake into cardiac cells and direct facilitation of neurotransmitter release through calcium-independent mechanisms. These effects may have both therapeutic implications and explain some of the drug's side effect profile.