D600, calcium channel blocking

In cardiac cells, there are two time-dependent outward currents which contribute to repolarization of the cell. Both of these outward currents may be decreased by calcium channel blocking drugs. Since an increase in the intracellular Ca2 + concentration activates one of the outward currents (7to), all the calcium channel blocking drugs should reduce Ito [ 159]. This has been shown with D600, nisoldipine and diltiazem [41-43, 159], The other time-dependent outward current (7X, delayed rectifier) is not calcium-activated [ 160]. Hume has found that D600, diltiazem and nisoldipine inhibit 7X in frog atrial cells [ 160]. However, a similar concentration of nisoldipine does not affect 7X in calf Purkinje fibres [43]. 

The calcium channel blockers have been found to affect several different subcellular processes (see Figure 7.2) and these effects may contribute to the pharmacological profile of the drugs. However, these actions are mainly seen at higher concentrations of the drugs than the concentrations required for calcium channel blockade. For example, high concentrations of D600, nitrendipine and verapamil have been shown to block the fast sodium channels present in cardiac tissue [44, 153-156], On the other hand, lower concentrations of verapamil do not decrease the maximum rate of depolarization of phase 0 of the action potential (Fmax) [156, 157], Neither diltiazem nor nisoldipine reduces Kmax [7,42]. Since influx of Na+ into the cell via the fast sodium... 

Simons and Pocock (1987) obtained similar results in a study of lead uptake by adrenal medullary cells. They found that metal influx was stimulated by depolarizing the cells in high external K, but that the stimulated influx was blocked by methoxyverapamil (D600) with an affinity that was higher than that for blockade of Ca " influx (0.4 vs. 4.7//M). Lead uptake was stimulated by the calcium channel agonist BAY-K8644. As was seen with cadmium, these results are consistent with the notion that voltage-dependent calcium channels could be an important route for the entry of lead into cells. Pb permeation was not affected if Cl was replaced by NO, an observation consistent with the relatively low affinity of Pb " for... 

---