Cellular electrophysiology of amlodipine: probing the cardiac L-type calcium channel

The electrophysiologic properties of amlodipine in single guinea-pig ventricular cells were investigated. The degree of ionization of the drug molecule was found to affect both the development of and the recovery from block of L-type calcium channels. Under alkaline conditions, when most of the drug is in a neutral form, the actions of amlodipine resemble previously described neutral dihydropyridine (DHP) compounds. Under these conditions, calcium channel block by amlodipine is reversibly regulated by cell membrane potential, i.e., block is more pronounced at voltages positive to -50 mV and completely relieved at voltages negative to -80 mV. When the drug molecule is ionized, block develops very slowly at positive membrane potentials and is very difficult to relieve on returning the membrane potential to more negative voltages. It is concluded that the degree of ionization of the drug molecule limits access to the DHP receptor and that the drug-bound receptor can be titrated by extracellular hydrogen ions. These results place limitations on the location of the DHP receptor within the cardiac sarcolemmal membrane.