Cupric ions (Cu(2+)), at concentrations above 0.03 mM, induced a progressive increase in the tonic contraction of guinea-pig ileal longitudinal muscle. Maximal contraction of 0.1 mM Cu(2+) attained a level above that of the 60-mM K(+)-induced tonic response, within 20 min of application. The tension induced by Cu(2+) persisted for more than several hours. Tetrodotoxin (3 x 10(-6) M) had no effect on the contraction induced by 0.1 mM Cu(2+). After incubation in a Ca(2+)-free medium, the ileal response to 0.1 mM Cu(2+) was lost. Nifedipine, a L-type Ca(2+) channel blocker, dose-dependently inhibited contractions induced by Cu(2+). As the duration of the first application of 0.1 mM Cu(2+) increased above 30 min, after washing with normal medium, the contractile response to a second application of 0.1 mM Cu(2+) decreased gradually. After 150 min of the first application of 0.1 mM Cu(2+), a second application of Cu(2+) could not evoke any contraction. After the application of 0.1 mM Cu(2+) for 150 min, when muscles were washed with a medium containing 1 mM EDTA, the response to 0.1 mM Cu(2+) returned to a greater extent in the normal Ca(2+) medium. In conclusion, Cu(2+) (0.1 mM) induced a maximal ileal tension above that of the K-induced tonic response within 20 min. The ileal contraction to Cu(2+) persisted for more than several hours and depended on extracellular Ca(2+) concentrations. It is possible that a part of Cu(2+), bound to a EDTA-inaccessible site, also has a tension inhibitory effect.