Figure 7.

Dynamics of DADs in the NM with O_TMgMg clamped and with the buffering variable O_C clamped (dashed). Pacing was maintained at a CL of 350 ms for 30 s, after which pacing was discontinued (time = 0). A. Voltage behavior for the two cases: clamping O_C prevents DADs following cessation of pacing. B. The initial depolarization when O_TMgMg is held constant is due to I_NaCa, which responds to an increase in [Ca²⁺]_i by increasing in magnitude. The upstroke of the DAD-induced AP therefore is slow early on, when it is controlled by I_NaCa, and then more rapid as the voltage reaches the threshold for I_Na activation. When O_C is held constant instead, I_NaCa does not depolarize the cell. C. Early calcium release from the SR occurs when O_TMgMg is clamped but not when O_C is clamped. The release current in this case is of a smaller magnitude but for a longer time and begins well before the AP upstroke. D. The gradual depolarization following the last paced beat when O_TMgMg is clamped coincides with a slow increase in [Ca²⁺]_i, which leads to the increase in the magnitude of I_NaCa. The calcium transient is much smaller when O_C is clamped instead, and it does not increase following cessation of pacing. E. The initial increase in [Ca²⁺]_i following cessation of pacing when O_TMgMg is clamped occurs when the sign of d[Ca²⁺]_i changes from negative to positive; here the plotted range of d[Ca²⁺]_i has been reduced to illustrate this occurrence. When O_C is clamped instead, no sign change occurs until the beginning of the upstroke of a paced beat. The sign of d[Ca²⁺]_i depends directly on the balance of three transmembrane currents, three intracellular calcium currents, and the rate of change of three calcium buffering variables, as well as indirectly on a number of other variables, all of which allows for numerous possibilities for enhancing or suppressing DADs.