BACKGROUND Brevetoxin (PbTx), taken from the earlier species name Ptychodiscus brevis, is a red algae toxin. It has been associated with clinically observed bronchoconstriction in nonasthmatics. In asthmatics, similar exposures may produce severe transient effects, sometimes requiring emergency treatment, thus suggesting that asthmatics are more sensitive to this toxin. As such, we have investigated potential mechanisms in vitro. METHODS Membrane potentials of in vitro airway smooth muscle (ASM) preparations were measured with a microelectrode before, during, and after the exposure to PbTx (0.01-1.2 microg/mL) in strip preparations (SPs) and cultured ASM reaggregate preparations. The latter preparation results in the disruption of normal peripheral nervous ASM associations through enzymatic dissociation of cells. RESULTS We observed an increased level of depolarization in asthmatic preparations at the same level of exposure. Exposure to PbTx produced concentration-dependent depolarization in both nonasthmatic and asthmatic in vitro SPs. In the former, responses did not occur in the presence of the blocking agents such as atropine or tetrodotoxin (TTX). In asthmatic SPs, atropine and TTX produced little effect, whereas verapamil blocked the PbTx-induced depolarization. The toxin was without effect in nonasthmatic cultured cells, whereas acetylcholine produced depolarization that was blocked in the presence of atropine, but not TTX or verapamil. In contrast, the toxin produced significant depolarization in cultured asthmatic ASM cells, which were unaffected by either atropine or TTX but were blocked by verapamil. CONCLUSIONS We propose that PbTx directly affects asthmatic ASM whereas the effect is neurally mediated in nonasthmatics.