A NEW-TYPE OF CA-CHANNEL MODULATION BY A NOVEL CLASS OF 1,4-DIHYDROPYRIDINES

Both Ca-antagonistic as well as Ca-agonistic 1,4-dihydropyridines (DHP s) have become extremely important tools to investigate the role of Ca -channels under various physiological and pathophysiological condition s. While Ca-antagonists stabilize the inactivated state of the Ca-chan nel without influencing the voltage dependent open and closed times, C a-agonists prolong the mean open time of the channel. We here report f or the first time the effects of a novel DHP, BAY Y 5959, which modula tes Ca-channel gating in a unique manner: It increases both the mean o pen time and the mean closed time of the Ca-channel by binding to the DHP receptor. This results in a reduced rate of Ca-current activation, an increased peak current, and a strongly prolonged tail current deca y. All these effects are strongly voltage dependent. Therefore it depe nds on resting membrane potential and shape of the action potential wh ether and how the Ca-influx into the cell is influenced. This novel mo de of action of BAY Y 5959 results in an interesting pharmacological p rofile: It has a strong positive inotropic effect in the heart without influencing vessel tone. Therefore the term Ca-promoter is suggested; it could become a new approach for the drug treatment of congestive h eart failure.