Previously we have described impaired myocardial conduction in patients receiving diltiazem and enflurane. The present study examines the possible mechanism(s) which may account for our clinical observation and presents methods of reversing adverse interactions. Nineteen mongrel dogs were randomized into two exposure groups: enflurane or chloralose anesthesia. Stepwise increasing doses of diltiazem were administered until predetermined endpoints were reached. Sinus and atrioventricular (AV) node function was assessed at all levels of diltiazem infusions, and after reversal drugs. Depression of AV nodal conduction and refractoriness after diltiazem administration was greater during enflurane anesthesia when compared with chloralose. There was severe sinus node dysfunction in enflurane-anesthetized animals. These effects were only reversed by isoproterenol. Patients may be at increased risk for severe sinus node depression when diltiazem is administered during enflurane anesthesia. This is due to a potent interaction between diltiazem and enflurane on the sinoatrial node.