Airway smooth muscle (ASM) contracts partly due to an increase in cytosolic Ca²⁺. In this work we found that the contraction caused by histamine depends on external Na⁺, possibly involving non-specific cationic channels (NSCC) and NCX. We performed various protocols using isometric force measurement of guinea-pig tracheal rings stimulated by histamine. We observed that force reached 53 ± 1% of control during external Na⁺ substitution by N-Methyl-D-glucamine⁺, whereas substitution by Li⁺ led to no significant change (91 ± 1%). Pre-incubation with KB-R7943 decreased the maximal force developed (52.3 ± 5.6 %) whereas pre-incubation with nifedipine did not (89.7 ± 1.8 %). Also, application of the non-specific NCX blocker KB-R7943 and nifedipine on histamine pre-contracted tracheal rings reduced force to 1 ± 3%, significantly different from nifedipine alone (49 ± 6 %). Moreover, non-specific NSCC inhibitors SKF-96365 and 2-Aminoethyl diphenyl borate reduced force to 1 ± 1% and 19 ± 7%, respectively. Intracellular Ca²⁺ measurements in isolated ASM cells, showed that KB-R7943 and SKF-96365 reduced the peak and sustained response to histamine (0.20 ± 0.1 and 0.19 ± 0.09 for KBR; 0.43 ± 0.16 and 0.47 ± 0.18 for SKF, expressed as mean of differences ). Moreover, Na⁺-free solution only inhibited the sustained response (0.54 ± 0.25). These data support an important role for NSCC and NCX during histamine stimulation. We speculate that histamine induces Na⁺ influx through NSCC that promotes the Ca²⁺ entry mode of NCX and Ca_V1.2 channel activation, thereby causing contraction.