A. Intracellular Biochemical Effects of Dihydropyridine Ca++/Calmodulin Antagonists. We have been studying the correlations between the inotropic effects of Ca++-antagonist dihydropyridines and their biochemical mechanisms of action. We have characterized the calmodulin-antagonists properties of these drugs by determining drug inhibition of smooth muscle myosin light chain kinase activity in vitro. We found that dihydropyridines with "Ca++-agonist" properties inhibited a calmodulin-dependent enzyme in a manner similar to and additive with that of their Ca++-antagonist analogues, implying that the inotropic properties of these drugs are unrelated to their calmodulin-antagonist properties. In a separate system, we demonstrated that dihydropyridine Ca++-antagonista stimulate Ca++ uptake in canine cardiac sarcoplamic reticulum in vitro increasing the ATP efficiency of Ca++ transport, and demonstrated also that this effect does not derive from the calmodulin-antagonist properties of the drugs. B. Regulation of Cardiac Sarcoplasmic Reticulum Ca++ Uptake. We have shown that a Ca++-activated, phospholipid-dependent protein kinase present in cardiac cells is able to phosphorylate a 27,000-dalton protein in cardiac sarcoplasmic reticulum and stimulate Ca++ uptake. This phosphorylation occurs in at least one site that is different from that phosphorylated by either cAMP- or calmodulin-dependent protein kinases.