Reversal of effects of acidosis on contraction of rat heart myocytes by CGP-48506.

In experiments reported here, we tested the ability of CGP-48506 to reverse the depressed cardiac contractility associated with hypercapnic acidosis in isolated rat cardiac myocytes. CGP-48506 is a cardiotonic agent that directly and specifically promotes the actin-cross-bridge reaction. Myocytes superfused at pH 6.8 demonstrated a significantly reduced extent of cell shortening, but an increase in the peak amplitude of the Ca2+ transient. Moreover, cells in acidosis showed small, but significant, decreases in time to peak shortening to 50 percent relaxation. Superfusion of the cells with 3, 7, and 10 micro-molar CGP-48506 restored the inhibited contractility as a function of concentration with no significant effects on the Ca2+-transient. Moreover, 10 micro-molar CGP-48506 completely reversed the depressed myocyte contraction associated with an increase in time to peak shortening and time to 50 percent and 75 percent relaxation. Our results indicate that the depression of contractility associated with acidosis is due to a reduced myofilament response to Ca2+, which can be overcome by agents working downstream from troponin C through a direct effect on the actin-myosin interaction.