The relative contributions of imidazoline-preferring receptors (IPR) and α2-adrenoceptors to hypotensive and bradycardic effects of intracisternal (i.e.) rilmenidine were investigated in conscious rabbits. We compared the antagonist potencies of two α2-adrenoceptor antagonists, 2-methoxy-idazoxan (0.001–10 μg/kg i.e.), which has very low affinity for IPR, and idazoxan (0.003–30 μg/kg i.e.), which has high affinity for blocking IPR. We also compared the i.e. effects of the antagonists on responses to α-methyldopa (α-MD), a drug with centrally acting α2-adrenoceptor agonist metabolites that have no affinity for IPR. Rilmenidine (22 μg/kg i.e.) and α-MD (400 μg/kg i.e.) produced similar decreases in mean arterial pressure (MAP) (ΔAMAP = −23 ± 2 and −24 ± 2%, respectively) and in heart rate (HR) (ΔHR = −11 ± 1 and −9 ± 2%, respectively, n = 30). The hypotension and bradycardia produced by α-MD and rilmenidine were completely reversed by 2-methoxy-idazoxan, but 2-methoxy-idazoxan was 16 and 9 times more potent at restoring MAP and HR, respectively, after α-MD than after rilmenidine. In contrast, idazoxan was more potent in reversing the hypotension elicited by i.e. injections of rilmenidine than that elicited by a-MD. Idazoxan, however, had no effect on rilmenidine-induced bradycardia, but did dose-dependently reverse the decrease in HR produced by α-MD. In separate experiments, we observed that the doses of each antagonist drug in themselves did not modify MAP nor HR significantly, but a 10-fold higher dose of idazoxan (300 μ /kg) caused immediate although brief hypertension and tachycardia. Thus, at “therapeutically relevant” doses, the preferential reversal of rilmenidine's hypotension by idazoxan as compared with 2-methoxy-idazoxan supports a more important contribution of IPR than of α2-adrenoceptors in the central cardiovascular effects of rilmenidine. Furthermore, since 2-methoxy-idazoxan at a high dose (10 μ /kg) completely reversed rilmenidine-induced hypotension suggests that the two receptor systems are likely to be in series along the same cardiovascular autonomic pathways in the brainstem.