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

International audienceThis study examined the effects of SR33805, a fantofarone derivative with reported strong Ca2+ ‐antagonistic properties, on the contractile properties of intact and skinned rat ventricular myocytes.On intact cells loaded with the Ca2+‐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 Ca2+ 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 (IC50=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 Ca2+‐activated force at the two‐tested sarcomere lengths (SLs), 1.9 and 2.3 μm.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 Ca2+‐sensitization of the myofilaments, particularly at 2.3 μm SL.In conclusion, despite its strong Ca2+‐antagonistic properties SR33805 increases cardiac cell contractile activity as a consequence of its Ca2+‐sensitizing effects. These effects are attributable to both an increase in the maximal Ca2+‐activated force and a length‐dependent Ca2+‐sensitization