Dihydropyridines bind approximately 1,000 times stronger to the inactivated state of the calcium channel than to resting channels, with block strongly modulated by membrane potential.
Dihydropyridines bind preferentially to the inactivated state of the calcium channel, explaining the contrast between electrophysiological and binding data.
We have investigated the mechanisms of blockade of calcium channel current by the dihydropyridines, e.g. nisoldipine, nitrendipine, and nicardipine. Membrane current was recorded in isolated calf Purkinje fibers using a two-microelectrode voltage-clamp technique, and voltage protocols were designed to identify voltage- and use-dependent block by these compounds systematically. Our results show that calcium channel blockade by dihydropyridine derivatives is strongly modulated by membrane potential. Block is more pronounced when current is measured from depolarized holding potentials, but in contrast to verapamil, this voltage-dependent block occurs in the absence of repetitive depolarizations. Use-dependent block by dihydropyridines is observed at pulse frequencies greater than 1 Hz. Our results suggest that dihydropyridines bind preferentially to the inactivated state of the calcium channel, and that the development of use-dependent block is related to the ionization constants of the compounds. Furthermore, binding is approximately one thousand times stronger to inactivated channels than to resting channels. This state-dependent difference in binding affinities may account for the previously reported contrast between electrophysiological and binding data for these compounds.
Sanguinetti et al. (1984) studied this question. Dihydropyridines (nisoldipine, nitrendipine, nicardipine) was evaluated on Voltage- and use-dependent block of calcium channel current. Dihydropyridines bind approximately 1,000 times stronger to the inactivated state of the calcium channel than to resting channels, with block strongly modulated by membrane potential.