Objective: The agonists of alpha2-adrenergic receptors are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or high-renin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (PO) or intracerebroventricular (ICV) clonidine treatment. Design and Methods: Adult male Dahl S rats fed 4% NaCl diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day PO) or via the infusion into the lateral brain ventricle (0.1 mg/kg/day ICV) for 4 weeks. Basal BP as well as the contributions of renin-angiotensin system or sympathetic nervous system (acute BP responses to intravenous injection of either captopril 10 mg/kg or pentolinium 5 mg/kg) to BP maintenance were determined in conscious cannulated rats at the end of the study. Results: Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin-dependent vasoconstriction in Ren- transgenic rats, whereas it lowered residual BP in Dahl rats. Conclusions: Our results indicate different mechanisms of antihypertensive action of clonidine depending on the route of its administration - central or systemical