SR33805, a Ca2+ antagonist with length-dependent Ca2+-sensitizing properties in cardiac myocytes

1 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. 2 On intact cells loaded with the Ca(2+)-nuorescent 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. 3 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 x 10(-5) M). 4 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 mum. 5 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 mum SL. 6 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.