Effects of K(+)- and Cl(-)-channel blockers on the muscle contraction of mouse diaphragm in response to direct electrical muscle stimulation were studied. K(+)-channel blockers (0.1-1 mmol/l 4-aminopyridine, 0.4-1.2 mmol/l uranyl nitrate and 2-30 mmol/l tetraethylammonium chloride) and a Cl(-)-channel blocker (0.01-0.03 mmol/l 9-anthracene carboxylic acid) increased the contractile amplitudes in a limited extent not to exceed over 50% of control. However, the sequential applications of two different channel blockers at a rather low concentration markedly increased the contractile responses mostly over 300% of control except the combination of 4-aminopyridine and uranyl nitrate. It appears that two K(+)-channel blockers synergistically exerted their effects rather than additionally in the regulation of muscle contractions. Investigation on the possible mechanism of the synergistic action of K(+)-channel blockers suggested that prolongation of action potential durations was in a linear correlation with the increased contractions. On the other hand, the contractile potentiation induced by combination of K(+)- and Cl(-)-channel blockers was attributed to the production of repetitive action potential firings (150 +/- 12 Hz) upon a single electrical stimulation. Similar to Cl(-)-channel blocker, low Cl- as well as low Ca2+ enhanced K(+)-channel blockers in producing contractile potentiation accompanied with stimulus-bound repetitive discharges. Tetrodotoxin at a concentration of 0.03 mumol/l which did not affect the twitches evoked by electrical stimulations completely inhibited the contractile potentiation induced by the combined application of K(+)- and Cl(-)-channel blockers.(ABSTRACT TRUNCATED AT 250 WORDS)