SR33805, a Ca 2+ antagonist with length‐dependent Ca 2+ ‐sensitizing properties in cardiac myocytes

This study examined the effects of SR33805, a fantofarone derivative with reported strong Ca 2+ ‐antagonistic properties, on the contractile properties of intact and skinned rat ventricular myocytes. On intact cells loaded with the Ca 2+ ‐fluorescent indicator Indo‐1, the application of low concentrations of SR33805 enhanced the amplitude of unloaded cell shortening and decreased the duration of cell shortening. Amplitude of the Ca 2+ transient was also decreased. These effects were accompanied with a shortening of the action potential and a dose‐dependent blockade of L‐type calcium current (IC 50 =2.4 × 10 −8 M ). On skinned cardiac cells, the application of a low SR33805 concentration (10 −8 M ) induced a significant increase in maximal Ca 2+ ‐activated force at the two‐tested sarcomere lengths (SLs), 1.9 and 2.3 μ m. The application of a larger dose of SR33805 (10 −6 –10 −5 M ) induced a significant leftward shift of the tension–pCa relation that accounts for Ca 2+ ‐sensitization of the myofilaments, particularly at 2.3 μ m SL. In conclusion, despite its strong Ca 2+ ‐antagonistic properties SR33805 increases cardiac cell contractile activity as a consequence of its Ca 2+ ‐sensitizing effects. These effects are attributable to both an increase in the maximal Ca 2+ ‐activated force and a length‐dependent Ca 2+ ‐sensitization.British Journal of Pharmacology (2003) 139 , 99–108. doi: 10.1038/sj.bjp.0705221