Summary—Tracheal strips from normal and actively sensitized guinea pigs were studied to determine the responses to serotonin (5‐hydroxytryptamine, 5‐HT; 1 nM – 0.1 mM) and ouabain (0.1 μM – 0.1 mM), and the effects of increasing the extracellular calcium (Cao) concentration on tonic contractions elicited by 5‐HT. Sensitized trachea exhibited an increased responsiveness and sensitivity to 5‐HT and ouabain. Increases in Caoto achieve final concentrations of 5, 10 and 20 mM caused concentration‐related relaxations of normal and sensitized tissues contracted to a similar plateau level with 5‐HT. Inhibition of the Na+/K+‐ATPase by ouabain (10 μM) reversed the effects of Caofrom relaxation to contraction in normal and sensitized tissues contracted with 5HT. Sensitized preparations showed reduced relaxations in response to Cao(10–20 mM), and sensitized, ouabain‐treated, trachea showed augmented contractions to Cao(10–20 mM) when compared to normal tissues. These results demonstrate a decreased membrane‐stabilizing effect of Caoin sensitized trachea and the implication of the Na+/K+‐ATPase in the regulation of membrane stability by Cao, suggesting a possible relevance to those mechanisms un