OBJECTIVE To evaluate effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 μg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 μg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 μg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao2 decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.