Rabbit perianesthetic morbidity and mortality are high due to unique physiologic and anatomic considerations. α2-adrenergic agonists are frequently used for sedation and anesthesia. However, these drugs can produce negative cardiovascular effects. A commercially available formulation licensed for sedation in dogs (Zenalpha®) combines medetomidine with vatinoxan, a peripherally acting α2-adrenergic antagonist. We evaluated this vatinoxan-medetomidine combination (2 mg/kg of vatinoxan-0.1 mg/kg of medetomidine) co-administered with ketamine (5 mg/kg) and butorphanol (0.5 mg/kg) (ZKB) in rabbits and compared the cardiopulmonary effects and quality of anesthesia to a previously described intramuscular anesthetic protocol using medetomidine (0.1 mg/kg), ketamine (5 mg/kg), and butorphanol (0.5 mg/kg) (MKB). Onset and duration of anesthesia as well as heart rate (HR), arterial blood oxygen saturation (SpO₂), body temperature, and blood pressure were measured and compared. Data was analyzed by using ANOVA and Friedman test (p < 0.05). Animals in group ZKB had a significantly lower mean arterial blood pressure (47 ± 2 mmHg vs 71 ± 5 mmHg, p < 0.01) and higher HR (206 ± 23 bpm vs 150 ± 14 bpm, p < 0.01) during anesthesia when compared to group MKB. ZKB anesthesia induction time was longer (470 ± 110 s vs 301 ± 44 s, p = 0.03) when compared to group MKB, while anesthesia and recovery times were similar between protocols. These findings suggest that the clinical applicability of the ZKB protocol at the tested dose may be limited due to its significant hypotensive effects.