Verapamil and dantrolene inhibit creatine transport in skeletal and cardiac myocytes

Creatine (Cr) and Phosphocreatine (PCr) are components of an energy buffering system in tissues with high metabolism like skeletal muscle, cardiac muscle and brain. Cr is synthesized by the liver, kidney and pancreas, and is also obtained from consumption of animal protein. Oral Cr supplementation has been commonly used by athletes and may also have therapeutic value in the treatment of Duchenne's disease, inflammatory myopathies, Parkinson's‐, Huntington's‐, and Alzheimer's disease, as well as Cr biosynthesis deficiency disorders. Myocytes lack Cr biosynthethic capabilities and depend on a Na + /Cl − ‐dependent transporter (CrT), to maintain their intracellular Cr content. Preliminary evidence suggested that Ca 2+ influences Cr transport. Following up on these observations, 14 C‐Cr uptake was measured in rat neonatal cardiac myocytes (RNCM), C2C12 or HL‐1 cells expressing the human CrT, treated with 5μM Verapamil (L‐type Ca 2+ channel blocker) or 1mM Dantrolene (RyR Ca 2+ channel blocker). Both Verapamil and Dantrolene reduced Cr transport in a time dependent fashion. 24hr incubation with either of these agents reduced C transport by 50% compared to controls in all cell types tested. Kinetic analysis indicates that the reduction in Cr transport is due to a decrease in K m . Further studies into the molecular mechanisms/pathways involved in this newly uncovered Ca 2+ regulation of Cr transport are warranted.