We examined the effects of antiarrhythmic drugs on the induction of cAMP by TSH (thyroid-stimulating hormone), using continuously cultured FRTL-5 rat thyroid cells. Group Ia antiarrhythmic drugs had no effect, but Group Ib antiarrhythmic drugs suppressed cAMP induction by TSH. These drugs suppressed cAMP induction in response to cholera toxin but did not inhibit TSH receptor binding or cAMP induction by forskolin. These results indicate that Group Ib antiarrhythmic drugs inhibit thyroid G-protein, resulting in a decrease in cAMP induction by TSH. We also examined the effect of antiarrhythmic drugs on K+ channels. Group Ia antiarrhythmic drugs had no effect on K+ channel activation by TSH and cAMP. On the other hand, Group Ib antiarrhythmic drugs suppressed K+ channel activation by TSH and cAMP. This indicates that the mechanism of suppression is not inhibition of TSH receptors or G-proteins but the direct suppression of K+ channels. Group Ib antiarrhythmic drugs inhibited thyroid Gs-protein and thyroid K+ channels. Considering the close relationship between G-protein and ion channels in the cardiac cell membrane, these different effects of Group Ia and Group Ib antiarrhythmic drugs on G-proteins and K+ channels are of interest. Further investigation is necessary to clarify the relationship between thyroid G-proteins and thyroid K+ channels.