Pulmonary veins (PV) make a significant contribution to total pulmonary vascular resistance. We investigated the extent and cellular mechanisms by which the intravenous anesthetics, propofol and thiopental, alter adenosine triphosphate-sensitive potassium (K⁺_ATP) channel relaxation in canine PV. The effects of K⁺_ATP channel inhibition (glybenclamide), cyclooxygenase inhibition (indomethacin), nitric oxide synthase inhibition (L-NAME), and L-type voltage-gated Ca²⁺ channel inhibition (nifedipine) on vasorelaxation responses to levcromakalim (K⁺_ATP channel activator) alone and in combination with the anesthetics were assessed. The maximal relaxation response to levcromakalim was attenuated by removing the endothelium and by L-NAME, but not by indomethacin. Propofol (10^-5, 3x10^-5 and 10^-4 M) and thiopental (10^-4 and 3x10^-4 M) each attenuated levcromakalim relaxation in endothelium-intact (E+) rings, whereas propofol (3x10^-5 and 10^-4 M) and thiopental (3x10^-4 M) attenuated levcromakalim relaxation in endothelium-denuded (E-) rings. In E+ rings, the anesthesia-induced attenuation of levcromakalim relaxation was decreased following pretreatment with L-NAME, but not with indomethacin. In E- strips, propofol (10^-4 M) and thiopental (3x10^-4 M) inhibited decreases in tension and intracellular Ca²⁺ concentration ([Ca²⁺]_i) in response to levcromakalim, and these changes were abolished by nifedipine. These findings indicate that propofol and thiopental attenuate the endothelium-dependent component of K⁺_ATP-induced PV vasorelaxation via an inhibitory effect on the nitric oxide pathway. Both anesthetics also attenuate the PV smooth muscle component of K⁺_ATP-induced relaxation by reducing the levcromakalim-induced decrease in [Ca²⁺]_i via an inhibitory effect on L-type voltage-gated Ca²⁺ channels.