The large B cells of bull-frog sympathetic ganglia are well known to be depolarized by slow synaptic transmission, muscarinic agonists, analogues of luteinizing hormone-releasing hormone (LHRH), and substance P. Voltage-clamp analysis shows that these actions result from two underlying mechanisms: inhibition of the M-current, a voltage-dependent potassium current; and in some cells, an inward current associated with an increase in conductance. The additional inward current appears as a voltage-insensitive change in the instantaneous conductance (i.e. apparent leak conductance). The additional inward current is typically slower in onset and offset than is M-current inhibition. It is typically seen for higher concentrations and longer durations of agonist application. In many cells, only a decrease in M-current can be demonstrated. Muscarine inhibits the M-current with 50% inhibition (I50) at 0.7 microM. At least 86% of the M-current is muscarine sensitive. At comparable concentrations, oxotremorine produces less M-current inhibition than does muscarine. Some analogues of teleost LHRH (T-LHRH) are more potent as M-current inhibitors than T-LHRH itself. Those peptides tend to act more slowly than T-LHRH. Substance P shows variable potency for M-current inhibition, with I50 s ranging from 2 nM to greater than 2 microM on different cells. The response to long applications of substance P desensitizes in some cells, which has not been observed for comparable applications of muscarinic or LHRH agonists. Other tachykinins (including substance K) inhibit the M-current. C-terminal fragments of substance P are ineffective, and M-current inhibition by substance P is not blocked by [D-Pro2,D-Trp7,9]- or [D-Arg1,D-Pro2, D-Trp7,9,Leu11] substance P. The slow muscarinic excitatory post-synaptic potential (e.p.s.p.) produces a graded inhibition of up to 90% of the M-current. Occasional cells show an additional inward current with an associated increase in conductance during the slow e.p.s.p. This effect is less marked than with exogenous muscarinic agonists. The late, slow e.p.s.p., which is produced by stimulation of high threshold C-fibre inputs and is resistant to cholinergic antagonists, also involves M-current inhibition. An additional inward current can be observed in some cells. M-current inhibition (by agonists or slow synaptic potentials) increases the number of spikes produced by a given depolarizing current, often allowing maintained firing. This action is not mimicked by equivalent depolarization, and is still seen when the cell is manually clamped to the original resting potential.(ABSTRACT TRUNCATED AT 400 WORDS)