Hexylcaine, an eater-type local anesthetic, was studied in guinea pig tracheal chains for its comparative effects on intrinsic tone and on responses to carbamylcholine, histamine and isoproterenol. Drug effects were recorded isotonically at a bath (PH of 7.5 (CO2, 5 per cent, and 25 mM bicarbonate) or (PH 6.75 (CO2, 5 per cent, and 5.75 mM bicarbonate), corresponding, respectively, to nonionized drug concentrations of 5.68 and 1.05 per cent of total hexylcaine. Low concentrations (10 to 3±10-4M) of hexylcaine produced an apparently competitive antagonism (P A2=4.95) of carbamylcholine. The extents of antagonism were not significantly different at the two values of experimental(PH, indicating that nonionized drug was not essential to the anticholinergic effect. In contrast, the concentration necessary for relaxation of intrinsic tone changed with (PH(10-3M at (PH 7.5; 3±10-3M at (PH 6.75), indicating that nonionized drug was essential, for access or for action, to the nonspecific relaxant effects of high drug concentrations. Hexylcaine, 3±10-4M(PH 7.5), increased the concentrations of carbamylcholine and histamine needed to produce a half-maximal response by 20.9 times and 3.6 times, respectively, and had no effect on responses to isoproterenol. The authors conclude that hexylcaine has selective and apparently competitive anticholinergic effects that are manifest at clinically relevant concentrations and are mechanistically distinct from the general depressant effects of higher concentrations.