BackgroundLike ischemic preconditioning, certain volatile anesthetics have been shown to reduce the magnitude of ischemia/ reperfusion injuryviaactivation of K+adenosine triphosphate (ATP)‐sensitive (KATP) channels. The purpose of this study was (1) to determine if ischemic preconditioning (IPC) and sevoflurane preconditioning (SPC) increase nitric oxide release and improve coronary vascular function, as well as mechanical and electrical function, if given for only brief intervals before global ischemia of isolated hearts; and (2) to determine if KATPchannel antagonism by glibenclamide (GLB) blunts the cardioprotective effects of IPC and SPC.MethodsGuinea pig hearts were isolated and perfused with Krebs–Ringer's solution at 55 mmHg and randomly assigned to one of seven groups: (1) two 2‐min total coronary occlusions (preconditioning, IPC) interspersed with 5 min of normal perfusion; (2) two 2‐min occlusions interspersed with 5 min of perfusion while perfusing with GLB (IPC+GLB); (3) SPC (3.5%) for two 2‐min periods; (4) SPC+GLB for two 2‐min periods; (5) no treatment before ischemia (control [CON]); (6) CON+GLB; and (7) no ischemia (time control). Six minutes after ending IPC or SPC, hearts of ischemic groups were subjected to 30 min of global ischemia and 75 min of reperfusion. Left‐ventricular pressure, coronary flow, and effluent NO concentration ([NO]) were measured. Flow and NO responses to bradykinin, and nitroprusside were tested 20–30 min before ischemia or drug treatment and 30–40 min after reperfusion.ResultsAfter ischemia, compared with before (percentage change), left‐ventricular pressure and coronary flow, respectively, recovered to a greater extent (P< 0.05) after IPC (42%, 77%), and treatment with SPC (45%, 76%) than after CON (30%, 65%), IPC+GLB (24%, 64%), SPC+GLB (20%, 65%), and CON+GLB (28%, 64%). Bradykinin and nitroprusside increased [NO] by 30 ± 5 (means ± SEM) and 29 ±4 nM, respectively, averaged for all groups before ischemia. [NO] increased by 26 ± 6 and 27 ± 7 nM, respectively, in SPC and IPC groups after ischemia, compared with an average [NO] increase of 8 ± 5 nM (P< 0.01) after ischemia in CON and each of the three GLB groups. Flow increases to bradykinin and nitroprusside were also greater after SPC and IPC.ConclusionsPreconditioning with sevoflurane, like IPC, improves not only postischemic contractility, but also basal flow, bradykinin and nitroprusside‐induced increases in flow, and effluent [NO] in isolated hearts. The protective effects of both SPC and IPC are reversed by KATPchannel antagonism.