Active sensitization of guinea pigs resulted in an increase in the responsiveness and sensitivity of tracheal strips to CaCl2 in K+-depolarized tissue (Emax 0.81 +/- 0.22 g/mm2 and pD2 2.35 +/- 0.10 in normal vs. 0.98 +/- 0.01 g/mm2 and 3.10 +/- 0.08 in sensitized tissue; p less than 0.05), KCl (Emax 0.62 +/- 0.08 g/mm2 and pD2 1.71 +/- 0.03 in normal vs. 0.91 +/- 0.04 g/mm2 and 2.00 +/- 0.01 in sensitized tissue; p less than 0.05) and histamine (Emax 0.70 +/- 0.06 g/mm2 and pD2 5.08 +/- 0.06 in normal vs. 0.94 +/- 0.09 g/mm2 and 5.80 +/- 0.16 in sensitized tissue; p less than 0.05) but not to caffeine 10 mM (20 degrees C, indomethacin 2.8 microM). Generation of responses to these agonists in nonsensitized tissues bathed in a Ca2+-free medium resulted in the abolition of KCl-induced contraction and partial inhibition of the responses to histamine (60% inhibition) and caffeine (40% inhibition). The contraction of sensitized tracheal strips in response to histamine in 0 calcium was greater than that obtained in nonsensitized tissues (0.48 +/- 0.02 g/mm2 vs. 0.28 +/- 0.04 g/mm2, respectively; p less than 0.05). The caffeine-induced contraction of sensitized tracheae was independent of extracellular calcium. These results suggest that a greater calcium entry and/or intracellular calcium release may be an alteration underlying hyperreactivity of sensitized tissues to spasmogens.