Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced
Karoline Horgmo Jæger1, Verena Charwat2, Samuel Wall3,2
1Simula Research Laboratory, Oslo, Norway. karolihj@simula.no.
Abstract:
In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug's efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug's inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug's overall efficacy. The data and fit models suggest that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.
Insights
Calcium channel blockers (CCBs) show variable efficacy in heart cells due to dynamic changes. Upregulation of calcium channels counteracts CCB effects, impacting drug response over time.
Area of Science:
- Cardiovascular Pharmacology
- Stem Cell Biology
- Computational Biology
Background:
- Calcium channel blockers (CCBs) are crucial in treating cardiovascular diseases.
- Variability in CCB efficacy, particularly nifedipine, is observed in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
- Temporal changes in CCB effects may relate to adaptive mechanisms within cardiomyocytes.
Purpose of the Study:
- To investigate if temporal variations in CCB efficacy are linked to adaptive changes in calcium ion channel expression.
- To explore the hypothesis that reduced intracellular calcium triggers calcium channel upregulation, counteracting CCB effects.
- To refine mathematical models to incorporate dynamic changes in ion channel expression.
Main Methods:
- Utilized a mathematical model simulating calcium ion channel expression regulation by intracellular calcium.
- Performed time-dependent measurements of hiPSC-CMs dynamics.
- Refined a mathematical model of myocyte action potentials to include dynamic calcium ion channel numbers.
Main Results:
- The mathematical model predicted that CCB-induced reduction in intracellular calcium leads to increased calcium ion channel expression.
- This upregulation of calcium channels was shown to attenuate the inhibitory effect of CCBs on calcium currents.
- Observed variations in CCB efficacy correlate with dynamic changes in protein expression within cardiac cells.
Conclusions:
- Dynamic changes in cardiac cells, specifically induced protein expression, can explain time-dependent variations in CCB efficacy.
- Understanding these adaptive mechanisms is crucial for interpreting calcium-based drug effects on the heart.
- Careful consideration of drug application timing is necessary to manage CCB efficacy and potential counteraction by cellular adaptations.
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