The Kv4.3 K+ channel is thought to underlie the Ca(2+)-insensitive transient outward current (I(to1)) in ventricular myocytes of canine and human heart and to contribute to the I(to1) in rat myocytes. It has been suggested that there is a second component of the transient outward current in some species that is contributed by a Ca(2+)-activated Cl- current (known as I(to2)). The evidence for the existence of the I(to2) current is based, in part, on the pharmacological effects of various Cl- channel blockers. To test for possible interactions between these compounds and I(to1), the effect of several different Cl- channel blockers on the Kv4.3 channel was examined. The fenamates (niflumic and flufenamic acid) were found to have large effects on the position of the steady state inactivation curve of the Kv4.3 channel. The disulfonic stilbenes (DIDS and SITS) had markedly different effects and were found to greatly reduce the rate of recovery from inactivation of the Kv4.3 channel without large changes in the position of the activation and steady state inactivation curves. Both classes of drugs produced an apparent blockade of the Kv4.3 channel under some recording conditions. Surprisingly, the closely related Kv4.2 channel was found to be markedly less sensitive to these drugs. Caffeine was found to block both the Kv4.3 and Kv4.2 channels to a similar extent. These nonspecific drug effects have implications for the study of the two components of the transient outward current and suggest that purely pharmacological criteria cannot be used to define the physiological role of I(to2).