Pulmonary veins (PV) make a significant contribution to total pulmonary vascular resistance. We investigated the cellular mechanisms by which the intravenous anesthetics propofol and thiopental alter adenosine triphosphate-sensitive potassium (KATP+) channel relaxation in canine PV. The effects of KATP+ 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 (KATP+ 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 after 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 KATP+ channel-induced PV vasorelaxation via an inhibitory effect on the nitric oxide pathway. Both anesthetics also attenuate the PV smooth muscle component of KATP+ channel-induced relaxation by reducing the levcromakalim-induced decrease in [Ca2+]i via an inhibitory effect on L-type voltage-gated Ca2+ channels.