AT(1) receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats

The effects of systemic treatment with the AT(1) receptor antagonist telmis artan on central effects of angiotensin II (Ang II), namely, increase in bl ood pressure, vasopressin release into the circulation, and drinking respon se, were investigated in conscious, normotensive rats. The central response s to i.c.v. Ang II (30 ng/kg) were measured at 0.5, 2, 4, and 24 h followin g acute i.v. or acute and chronic oral telmisartan application, At a dose o f 10 mg/kg i.v., the drinking response to i.c.v. Ang II was completely bloc ked over 4 h, while the presser response and the release of vasopressin in response to i.c.v. Ang II were blocked by 60 to 80%. The inhibition of the centrally mediated presser and drinking response to Ang II was sustained ov er 24 h. The lower doses of telmisartan (0.3 and 1 mg/kg) significantly inh ibited the Ang II-induced actions over 4 h. A consistent 24-h inhibition of the central responses to i.c.v. Ang II was obtained after acute and chroni c oral treatment with 30 mg/kg telmisartan. Oral treatment with 1 and 3 mg/ kg telmisartan produced a slight but inconsistent inhibition of the central actions of Ang II. Telmisartan concentrations measured in the cerebrospina l fluid following 8 days of consecutive daily oral treatment (1-30 mg/kg) r anged from 0.87 +/- 0.27 ng/ml (1 mg/kg/day) to 46.5 +/- 11.6 ng/ml (30 mg/ kg/day). Our results demonstrate that, following peripheral administration, the AT, receptor antagonist telmisartan can penetrate the blood-brain barr ier in a dose- and time-dependent manner to inhibit centrally mediated effe cts of Ang II.