Various mechanisms can account for selective inhibition bycalciuminflux blocking drugs ofsmoothmusclecontractile activity. Diltiazem inhibitscalciuminflux activated by membrane depolarization as well as alpha adrenergic receptor stimulation. Diltiazem does not inhibit intracellularcalciumrelease nor cause netcalciumextrusion up to concentrations of 10(-5) M. As with othercalciuminflux blocking agents, diltiazem is a potent inhibitor for modes of activation that depend entirely on the presence of extracellularcalcium. Thecalciuminflux was found to be mediated by at least three different pathways: one activated by depolarization and highly sensitive to D-600, a second activated by norepinephrine and less sensitive to D-600, and a third "passive leak," that is insensitive to D-600 and accounts forcalciumpermeability in the resting state. Molecular differences among these variouscalciumchannels may provide the basis for specificity ofactionof thecalciuminflux blocking agents.