Membrane Potential and Nisoldipine Block of Calcium Channels in the Heart: Interactions with Channel Gating

Summary

Dihydropyridine compounds are an important group that serve as powerful tools for probing the structure and function of calcium channels in a variety of tissues as well as being important therapeutic agents. The 1,4-dihydropyridine calcium channel antagonists such as nisoldipine and nitrendipine are among the most patent inhibitors of Ca influx in cardiac and smooth muscle cells. The actions of these drugs have been shown to depend very strongly on the membrane potential of the cell. The drugs inhibit current more potently at depolarized membrane potentials. This activity has been suggested to be due to an interaction with the inactivated state of these channels, which is favored at depolarized membrane voltages. Another series of structurally related dihydropyridines (calcium channel agonists) has been shown to enhance currents through calcium channels primarily by prolonging the mean open time of the channels [5]. However, even the activity of this group of drugs depends on membrane potential, and at positive voltages the agonists can promote antagonist-like effects [18]. We are presently investigating the mechanisms behind these voltage-dependent actions. Our experiments are designed to determine whether antagonists such as nisoldipine do, in fact, interact with the inactivated state of the calcium channel and to test the possibility that antagonism and agonism are mediated by distinct receptors, access to which depends on the state of the channel and, in turn, membrane potential.