Vol. 298, Issue 1, 62-70, July 2001

AT₁ Receptor Antagonist Telmisartan Administered Peripherally Inhibits Central Responses to Angiotensin II in Conscious Rats

P. Gohlke , S. Weiss, A. Jansen, W. Wienen, J. Stangier, W. Rascher, J. Culman and T. Unger

Institute of Pharmacology, Christian-Albrechts University of Kiel, Kiel, Germany (P.G., S.W., A.J., J.C., T.U.); German Institute for High Blood Pressure Research, Heidelberg, Germany (P.G., J.C., T.U.); Boehringer Ingelheim, Biberach an der Riss, Germany (W.W., J.S.); and Department of Paediatrics, University of Erlangen-Nürnberg, Erlangen, Germany (W.R.)

The effects of systemic treatment with the AT₁ receptor antagonist telmisartan on central effects of angiotensin II (Ang II), namely, increase in blood pressure, vasopressin release into the circulation, and drinking response, were investigated in conscious, normotensive rats. The central responses to i.c.v. Ang II (30 ng/kg) were measured at 0.5, 2, 4, and 24 h following acute i.v. or acute and chronic oral telmisartan application. At a dose of 10 mg/kg i.v., the drinking response to i.c.v. Ang II was completely blocked over 4 h, while the pressor 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 pressor and drinking response to Ang II was sustained over 24 h. The lower doses of telmisartan (0.3 and 1 mg/kg) significantly inhibited 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 chronic 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 cerebrospinal fluid following 8 days of consecutive daily oral treatment (1-30 mg/kg) ranged 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 AT₁ receptor antagonist telmisartan can penetrate the blood-brain barrier in a dose- and time-dependent manner to inhibit centrally mediated effects of Ang II.