The effects of different compounds that inhibit the isolated plasma-membrane Ca2 § on the cytosolic free Ca z + concentration ([Ca 2 +]i) and on the corresponding force development have been examined in smooth muscle of the longitudinal layer of the guinea-pig ileum. F-, in the presence of A13 +, induced an increase of the resting force and of the amplitude of the superimposed phasic contractions. The increase of resting force was associated with an increased level of basal [Ca2+]i while the phasic contractions were accompanied by concomitant oscillations in [Ca2+]i. Comparable contractions could be induced by vanadate and the calmodulin antagonist calmidazolium. The oscillations of [Ca z +]5 and of force elicited by A1F2 were not modified by adrenergic or cholinergic blocking agents but were inhibited by verapamil. These phasic contractions were not affected by depleting the intracellular Ca 2 + stores with ryanodine. This finding excludes a cytosolic origin of these oscillations. However, hyperpolarization and complete depolarization of the cells inhibited the oscillations. It is concluded that A1F2, vanadate and calmidazolium induce cytoplasmic Ca 2 + oscillations possibly by acting at the plasma membrane. Indeed all these substances affect by different mechanisms the isolated plasma-membrane CaZ+/MgZ+-ATPase. The generation of membrane-linked Ca 2 + oscillations could therefore be related to an inhibition of the plasma-membrane Ca 2+ pump resulting in an increase of [Ca 2 +]i" This change in [Ca 2 +]i could be responsible for the pronounced changes of the electrical and mechanical activity of this tissue.