CELLULAR BIOLOGY OF ANTIANGINAL AGENTS ; DEVELOPMENT AND EVALUATION OF NEW DRUGS.

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The purposes of this study are to (i) clarify the mechanisms of signal transductions in various vascular smooth muscle, (ii) determine the effect of well known antianginal agents on the signal transduction, and (iii) develop new antianginal drugs. (1) Using front-surface fluorometry and fura-2-loaded strips of the coronary artery of the pig, the effect of nitroglycerin (NG) on cytosolic Ca concentration, (Ca)i, and on tension development were measured simultaneously. NG actively reduced both (Ca)i and tension, irrespective of whether strips were at rest or under stimulation with either high-K-depolarization or histamine. For NG-induced relaxation, the extent of the decrease in tension was greater than that expected from the reduction of (Ca)i based on the (Ca)i-tension relation observed with K-depolarization. In the absence of extracellular Ca, NG depleted stored Ca and also inhibited the release of Ca from histamine-sensitive stores. Thus, NG relaxes the coronary artery of the pig by reducing (Ca)i. In addition, and independent of the (Ca)i change, a second messenger, positively cyclic GMP, may directly influence the contractile elements during NG-induced relaxation. (2) Diltiazem, a Ca-antagonist, in a concentration lower than 10 uM, inhibited extracellular Ca-dependent increases in (Ca)i (Ca influx through Ca channels), and secondarily caused decreases in tension development which was proportional to (Ca)i decrease, with no effect on Ca-sensitivity of the contractile elements. At high concentration, 0.1 mM, diltiazem inhibited Ca-release from intracellular store sites, possively by inhibiting binding of the agonist at receptor sites. (3) It was found that a newly synthetized inhibitor of phosphodiesterase could inhibit Ca-influx through mechanisms mediated by opening of the ATP-sensitive K channels, and also could release relaxing factor from endothelial cells.