1 The ability of cyproheptadine (Cph) to inhibit membrane translocation of calcium in smooth muscle was investigated by studying the drug's action on contraction, electrical activity and calcium influx in the guinea-pig taenia coli.2 Cph >/= 10(-6)M reduced the amplitude of normal spontaneous contractions and concurrently decreased the number of action potentials occurring with each slow-wave of depolarization (sucrose-gap recordings). These inhibitory effects of Cph were antagonized by increasing the medium [Ca] three fold to 7.68 mM.3 Intracellular recordings showed that Cph >/= 2 x 10(-6)M decreased the amplitude and extended the duration of the action potential. These effects were only partially reversible in normal medium whereas large overshooting action potentials were again seen in 7.68 mM Ca medium.4 High frequency mechanical activity was produced by inclusion of veratridine 5 x 10(-6)M in the perfusate. Low concentrations of Cph (>/= 10(-7)M) reduced the amplitude of such contractions at a faster rate than they did normal spontaneous contractions.5 At concentrations between 10(-7) and 10(-6)M, Cph fully reduced the tonic component of contractions elicited in 112 mM isotonic KCl whilst having little or no effect on either (i) the initial phasic KCl contraction or (ii) the ;repolarization contracture' normally produced on wash-out of the KCl or (iii) the spontaneous contractions before and after KCl treatment. In contrast, at Cph 2 x 10(-6)M, the repolarization contracture, as well as the isotonic KCl contraction, was totally blocked whereas spontaneous contractions were still unaffected. Progressively higher Cph concentrations inhibited all components of this contractile cycle.6 Dose-response curves for the rate of drug-induced relaxation of tonic contractures produced in hypertonic 42.7 mM high-potassium medium, showed the calcium antagonistic potency of Cph to be intermediate between that of chlorpromazine and D600. The minimum Cph concentration for effect lay between 1 and 5 x 10(-7)M, and the effects of Cph 2 x 10(-6)M (approximately the ID(50)) were totally antagonized by 12.8 mM Ca.7 By means of a lanthanum wash procedure, Cph >/= 2 x 10(-6)M was found to decrease the (45)Ca uptake occurring into strips of taenia coli in normal medium, although the maximum effect (at Cph 10(-5)M) amounted to only 25% inhibition of the uptake occurring into control strips (also found with D600). The increased uptake occurring in hypertonic 44.7 mM high-potassium medium was inhibited in a dose-dependent manner by Cph 1 x 10(-7)M.8 The results are consistent with an action of Cph in reducing the flow of Ca(2+) through voltage-dependent Ca channels in the smooth muscle cell membrane. It is suggested that the interaction of Cph molecules with such sites is dependent upon membrane potential as well as drug concentration.