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.


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.
Gohlke
Peter
P
Institute of Pharmacology, Christian-Albrechts University of Kiel, Germany. peter.gohlke@pharmakologie.uni-Kiel.de
Von Kügelgen
Sebastian
S
Jürgensen
Thomas
T
Kox
Thomas
T
Rascher
Wolfgang
W
Culman
Juraj
J
Unger
Thomas
T
D000284:Administration, Oral; D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D008845:Microinjections; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D001127:Arginine Vasopressin; C077793:candesartan cilexetil