Objective: Pulmonary epithelial cells are permanently exposed to mechanical forces such as shear force and stretch – under physiological as well as pathophysiological conditions. Since knowledge about the impact of these forces on pulmonary epithelial ion transport is scarce, the present study addresses whether ATP-sensitive K⁺ channels (KATP might be involved in the response obtained by mechanical stimulation of pulmonary epithelia. Methods: Freshly isolated Xenopus lung preparations were used for Ussing chamber recordings. Lung preparations were exposed to a hydrostatic pressure (HP) gradient (increased pressure apical side) and the short-circuit current (I_SC) was recorded. Further, RT-PCR experiments were performed to verify the expression of KATP channel subunits in lung homogenates. Results: Increased HP resulted in a decrease of ISC (20%, P < 0.001). Interestingly, the HP-induced effect was decreased by glibenclamide (100 mM), an inhibitor of KATP channels. To exclude side effects of glibenclamide experiments with the high selective KATP channel inhibitor HMR1098 were conducted. HMR1098 also prevented the decrease of ISC as obtained under control conditions. Activation of KATP channels as observed might be due to: (i) decreasing intracellular ATP concentrations, (ii) direct activation of KATP channels via mechanical stress. Brefeldin A, which is supposed to abolish ATP release via exocytose, did not prevent the reduction of I_SC in response to HP. RT-PCR experiments performed with lung homogenates confirmed the expression of Kir2.1 and Kir6.1, the subunits forming the pore of KATP channels. Conclusion: The present data indicate that KATP channel subunits are expressed in Xenopus lung and there is evidence that these channels are functionally expressed in pulmonary epithelial cells. Further, KATP channels might be part of a mechanosensory complex in pulmonary epithelial cells and responsible to mediate ion and fluid reabsorption under native, dynamic conditions.