Imipramine, amitriptyline, mianserine, maprotiline, and trazodone are five widely used antidepressant drugs with different chemical structures. Imipramine and amitriptyline are tricyclics, mianserine and maprotiline are tetracyclics, and trazodone is a triazolopyridine derivative. We studied the effects of these drugs on the transient outward K+ current (Ito) and the interaction mechanisms within the drug molecules and the channel-binding site. The transient outward K+ current is mainly responsible for action-potential repolarization in the rat ventricle, and all of the five drugs studied block Ito, but in different manners. Cyclic drugs block Ito in the open state of the channel with very little block in the rested or inactivated states or both. Trazodone blocks the channel in a state-independent manner. From these results, we suggest that a relation exists between drug structure and preference for the different channel conformations.