1. Inhibitory actions of the external divalent cations, Cd2+, Ni2+, Mn2+ and Co2+ on carbachol (CCh)-induced inward current (Ins,ACh) were investigated in caesium aspartate-loaded single longitudinal smooth muscle cells of guinea-pig ileum, using a rapid solution-switching device, under voltage-clamped conditions. 2. Cd2+ (20-1000 microM), when added to the external solution, reduced Ins,ACh rapidly and reversibly. This effect occurred dose dependently, the relationship being adequately described by a Michaelis-Menten equation with a Hill coefficient (n) of 1.0 and a dissociation constant (Kd) of 98 microM. 3. The inhibitory action of Cd2+ was associated neither with agonist concentration (CCh) nor with changes in reversal potential, and was voltage independent. 4. The appearance and removal of the effect of Cd2+ were both rapid (a few hundred milliseconds), in sharp contrast with a relatively slow time course of atropine or CCh action (of the order of seconds). 5. Other divalent cations (Ni2+, Mn2+, Co2+, Mg2+) applied externally also suppressed Ins,ACh, but less potently. The sequence of apparent potency was Cd2+ (98 microM) greater than or equal to Ni2+ (131 microM) much greater than Co2+ (700 microM) greater than or equal to Mn2+ (1000 microM) much greater than Mg2+ (approximately 10 mM). 6. External Ca2+ increased Ins,ACh dose dependently and antagonized the inhibitory effect of Cd2+. However, this effect may not be a simple competition with Cd2+. 7. These results show that external divalent cations strongly modulate Ins,ACh channels, possibly through direct interaction with the channel protein.