Effects of orally applied candesartan cilexetil on central responses to angiotensin II in conscious rats

OBJECTIVE: In the present study, we investigated the ability of the peripherally administered angiotensin II type 1 (AT1) receptor antagonist, candesartan cilexetil, to block central effects of angiotensin II (Ang II) in conscious rats. DESIGN AND METHODS: Candesartan cilexetil was administered orally by gavage at doses of 0.1, 1, 10 and 30 mg/kg. Drinking response, pressor response and release of vasopressin into the circulation following intracerebroventricular (i.c.v.) Ang II (10 or 100 ng) were measured at 0.5, 2, 4 and 24 h following the drug application. The same parameters were measured after chronic treatment with candesartan cilexetil for 1 week. In a separate experiment, the release of vasopressin induced by microinjection of Ang II (100 ng) into the paraventricular nucleus (PVN) was determined 4 h after oral administration of candesartan cilexetil (1 mg/kg) or vehicle. RESULTS: Oral treatment with candesartan cilexetil inhibited all central responses to i.c.v. Ang II in a dose- and time-dependent manner. The Ang II-induced responses were inhibited 4 h after acute or chronic treatment with 0.1 mg/kg candesartan cilexetil, but had returned to control levels 24 h after drug application. In contrast, the highest dose of candesartan cilexetil (30 mg/kg) nearly abolished the central responses to Ang II for 24 h. Candesartan cilexetil completely blocked vasopressin release into the circulation induced by Ang II microinjection into the PVN. CONCLUSIONS: Our results demonstrate that the AT1 receptor antagonist, candesartan cilexetil, very effectively inhibits the centrally mediated effects of Ang II upon peripheral application.