The contractile response of smooth muscles to spasmogens can be divided into two components by modifying the extracellular Ca2+ concentration. The phasic component depends on the mobilization of Ca2+ from intracellular stores whereas the tonic component depends, to a large extent, on the influx of extracellular Ca2+. The present study was designed to investigate the effect of ketamine on the tonic response to carbachol or histamine in the guinea pig trachea. Tracheal spirals from female guinea pigs were mounted in organ baths filled with aerated physiological buffer, and their isometric tension was measured. The phasic response to 10−7m carbachol or 10−5m histamine in Ca2+ -free, ethylene glycol-bis(β-aminoethyl ether)-N, N,N',N'-tetraacetic acid-containing buffer and the tonic response to each spasmogen after restoring [Ca2+] in the buffer was measured in the absence or presence of ketamine. In the presence of normal physiological buffer, ketamine decreased the contractions induced by carbachol or histamine in a dose-dependent fashion. No measurable phasic response to either carbachol or histamine was obtained in our preparation. Ketamine (5 × 10−5m−10−3m) reduced the tonic response to 10−7m carbachol to 79.5±2.7−4.3±0.7% of the response without ketamine. Similarly, ketamine (5 × 10−4m−2 × 10−3m) decreased the tonic response to 10−5m histamine to 80.7±3.9−23.0±3.2% of the response in the absence of ketamine. Our findings support the hypothesis that ketamine inhibits the paracrine agent-induced contractions of smooth muscles by interfering with the influx of extracellular Ca2+ or with an intracellular event(s) requiring extracellular Ca2+.