@article{17689,
  author = {Karoline J{\ae}ger and Verena Charwat and Samuel Wall and Kevin Healy and Aslak Tveito},
  title = {Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?},
  abstract = {In the initial hours following the application of the calcium channel blocker (CCB) nifedipine tomicrotissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug{\textquoteright}sefficacy. Here, we investigate the possibility thatthese temporal changes in CCB effects are associated with adaptations in the expression of calciumion channels in cardiomyocyte membranes. To explore this, we employ a recently developedmathematical model that delineates the regulation of calcium ion channel expression by intracellularcalcium concentrations. According to the model, a decline in intracellular calcium levels below acertain targetlevel triggers an upregulation of calcium ion channels.Suchan upregulation, if instigatedby a CCB, would then counteract the drug{\textquoteright}s inhibitory effect on calcium currents. We assess thishypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existingmathematical model of myocyte action potentials incorporating the dynamic nature of the number ofcalcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellularcalcium concentrations leads to a subsequent increase in calcium ion channel expression, therebyattenuating the drug{\textquoteright}s overall efficacy. The data andfit models suggest that dynamic changes incardiac 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 unlesstimings of applications are carefully considered.},
  year = {2024},
  journal = {npj Systems Biology and Applications},
  volume = {10},
  pages = {22},
  publisher = {Springer Nature},
  url = {https://rdcu.be/dz5CW},
  doi = {https://doi.org/10.1038/s41540-024-00347-3},
}