We have studied the effects of CA++ antagonist drugs which are able to bind to calmodulin on calmodulin-mediated processes involved in muscle contraction including smooth muscle myosin light chain kinase activation and cardiac saroplasmic reticulum Ca++ uptake. In a system of purified turkey gizzard contractile proteins, the Ca++ antagonists felodipine, nitrendipine, and verapamil inhibited myosin light chain kinase activity with I.C.50's of 9.8 x 10 to the -6M, 5.6 x 10 to the -5M, respectively. This inhibition could not be overcome by increasing the Ca++ concentration. Binding studies showed a Kapp (nitrendipine/calmodulin) of 5.5 x 10 to the -5M, which correlates well with inhibition of enzyme activity and suggests that inhibition occurs via binding of drugs to calmodulin and blocked calmodulin-dependent enzyme activation. We are currently studying the effect of Ca++ antagonists on Ca++/calmodulin binding via equilibrium dialysis. In a microsomal preparation, derived from canine cardiac sarcoplasmic reticulum, we have examined the effects of Ca++ antagonists on oxalate-stimulated Ca++ uptake as quantified by changes in Arsenazo III absorbance. The sole effect of verapamil is inhibition of Ca++ uptake at high drug concentrations. Felopdipine likewise inhibits Ca++ uptake at high concentrations, but at lower concentrations causes marked stimulation of Ca++ uptake. Similar stimulation is seen with nitrendipine. We are currently attempting to learn the mechanism through which these drugs effects occur.