1 The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2 In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant e ects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) e ects. 3 To study CVS e ects over a wide range of doses with minimal CNS and other in¯uences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (*50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 mmol (&2.5 mg) in 8 mmol increments, to either a fatal outcome or a 40 mmol (&12.5 mg) maximum. 4 All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular ®brillation: four of six with bupivacaine (mean+s.e.mean actual fatal dose: 21.8+6.4 mmol), ®ve of seven with levobupivacaine (22.9+3.5 mmol), four of six with ropivacaine (22.9+5.9 mmol). No signi®cant di erences in survival or in fatal doses between these drugs were found. 5 The ®ndings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the di erences between the drugs found with intravenous dosage. British Journal of Pharmacology (2001) 132, 649 ± 658 Keywords: Local anaesthetics; bupivacaine; levobupivacaine; ropivacaine; coronary circulation; myocardial contractility; ventricular arrhythmias; sheepAbbreviations: ANOVA, analysis of variance; CI, con®dence interval; CO, cardiac output; dP/dt max , maximum value of the ®rst derivative of LVP; E max , magnitude of peak e ects; HR, heart rate; i.v., intravenous: LCA, left coronary artery; LVP, left ventricular pressure; MED, mean e ect di erence, SED 5 and SED 10 , sum of the e ect di erences, respectively, to 5 and 10 min; PVC, premature ventricular contractions; QTc, HR corrected QT interval; R-bupivacaine or dexbupivacaine, (+)-R-bupivacaine; S-bupivacaine or levobupivacaine, (7)-S-