Intracerebroventricular administration of angiotensin type 1 (AT1) receptor antisense oligonucleotides attenuate thirst in the rat

Abstract

The central actions of the peptide hormone angiotensin II (AngII) are importantly involved in body fluid homeostasis. Included amongst these actions is a potent dipsogenic response that has been implicated in the thirst that develops during many forms of extracellular dehydration. The use of highly selective receptor antagonists has revealed that the Type 1 (AT1), and not the Type 2 (AT2), AngII receptor subtype mediates this drinking response. More recently, antisense oligonucleotides specific for the AT1 receptor have been developed and after intracerebroventricular (i.c.v.) administration, they significantly reduce the dipsogenic response elicited by a similar injection of AngII. In the present study AT1 antisense oligonucleotides were used to further investigate their effect on experimentally induced thirst in the rat. In addition, immunohistochemical analysis of biotin-labeled oligonucleotides was performed in order to correlate the behavioral effects of the oligonucleotides with their distribution in the brain. The results demonstrated that the antidipsogenic effects of the oligonucleotides were dose and time-dependent and were limited to those thirst challenges that involve activation of the renin-angiotensin system. Collectively, these results demonstrate the efficacy and behavioral specificity of these oligonucleotides, as well as their utility in investigating the physiological role of cerebral AngII receptor subpopulations in various models of thirst.