Summary: Calcium antagonists inhibit vascular smooth muscle activity in a way that depends on the properties of the inhibitory agent, the type of effector tissue studied, and the applied means of activation. In the experiments described here, the phasically active portal vein of the rat and the essentially tonic aortae of the rat and the rabbit were examined. They were exposed to reduced external calcium ion concentration (from 2.5 mM to 0.6 and 0.2 mM) and to the structurally different calcium antagonists felodipine, verapamil, and diltiazem in “therapeutic” and 1,000-fold higher concentrations. The tissues were pretreated for 1 h with the intended [Ca2+]0 or the calcium antagonist concentration under study. Cumulative concentration-effect curves to noradrenaline (NA) were obtained in the control situation at reduced [Ca2+]0 and at two concentrations of a calcium antagonist. In the rat portal vein, low doses of all calcium antagonists suppressed all NA responses but caused no rightward shift of the concentration-effect curve. High doses of the calcium antagonist abolished portal vein spontaneous activity and reduced the maximum NA response to some 10% of control. In the rat portal vein, reduced [Ca2+] caused rightward shifts of the NA concentration-effect curve without (0.6 mM) or with (0.2 mM) reduced maximum NA responses. In the rat aorta, reduced [Ca2+]0 and the calcium antagonists caused progressive rightward shifts of the curves with progressive reductions in the maximum NA responses. In the rabbit aorta, there was no effect on NA responses with reduced [Ca2+]0 or of the calcium antagonists in “therapeutic” concentrations; verapamil and diltiazem, but not felodipine, caused significant effects in the 1,000-fold higher concentrations. It is concluded that calcium antagonists and reduced [Ca2+]0 may inhibit the adrenergic responses of vascular smooth muscle in vitro in various ways depending on type of tissue, means of activation, and concentration of the agonist as well as the antagonist. In the phasically active smooth muscle of the portal vein, calcium antagonists reduce spontaneous contractile activity and all graded NA responses to the same relative extent, indicating a site of action either at the level of membrane excitation and/or at the level of the contractile process.