Anesthesia with sevoflurane is accompanied by vasodilatation. This could be due to the effects of sevoflurane on endothelium-dependent relaxation. We measured muscle tension of isolated human omental arteries and veins in response to substance P or glyceryl trinitrate in the presence of sevoflurane (0%, 1%, 2%, or 4%). Vascular levels of guanosine 3', 5'-cyclic monophosphate were measured with enzyme-linked immunosorbent assay. Substance P induced an endothelium- and concentration-dependent relaxation in omental vessels that was not affected by sevoflurane. In the presence of L-N(G)-nitroarginine methyl ester (nitric oxide synthase inhibitor), KCl (prevention of hyperpolarization), or both, sevoflurane at 4% enhanced the relaxation in the arteries (P < 0.05). In the vein segments, the relaxation was enhanced by sevoflurane at 4% in the presence of KCl and 2% and 4% in the presence of both L-N(G)-nitroarginine methyl ester and KCl (P < 0.05). The glyceryl trinitrate-induced endothelium-independent relaxation was enhanced by sevoflurane at 4% in both artery and vein segments (P < 0.05). Substance P increased the levels of guanosine 3', 5'-cyclic monophosphate similarly in the presence and absence of sevoflurane. These results show that sevoflurane, in contrast to its effect in animal models, promotes endothelium-dependent relaxation in human omental arteries and veins via an enhancement of the smooth muscle response to relaxing second messengers.