CA ANTAGONISTS AND CA CHANNELS

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The long-term objectives and specific aims are to elucidate the mechanisms by which Ca antagonistic agents exert their effects on Ca channels. In many excitable cells, the entry of Ca ions can be inhibited by verapamil, D-600, diltiazem and dihydropyridine compounds such as nifedipine and nitrendipine. These drugs are often called "Ca antagonists" or "Ca channel blockers" and are clinically important because they exert antiarrhythmic and antianginal actions. The therapeutically relevant targets for these agents are Ca channels in the cell membrane of myocardial fibers and vascular smooth muscles (particularly of the coronary artery). Little is known about how the Ca antagonistic agents interact with and block the Ca channels. One hypothesis concerning their mechanism of action is that the channels must open before they can be blocked by these compounds. Significant advances in understanding the mechanism of these drugs are now possible through the use of the patch clamp technique for single channel recording, which enables us to directly obtain information about drug-channel interactions at the single channel level. In the proposed research, isolated ventricular cells of the adult guinea pig heart and cultured chick myocytes will be used as the materials since the patch clamp technique is applicable to them. The blocking effects of the three major classes of organic Ca antagonists, represented by verapamil or D-600, diltiazem and nitrendipine will be examined on the whole cell variation of the patch clamp technique. In these experiments, the frequency (use) dependence, voltage dependence and dose-response of block and possible change in the kinetics of Ca current induced by drugs will be investigated. These will provide us with the picture of "macroscopic" effects with which "microscopic" effects obtained by single channel recording can be compared. The mode of the drug action will be analyzed by the single channel recording. The agents are expected to interact preferentially with open channels. The analyses are based on measurement of the open time, blocked time, the burst period, and voltage dependence of block. This research is expected to provide useful information about the clinical application of Ca antagonists.