ANTISENSE OLIGONUCLEOTIDE TO AT(1) RECEPTOR MESSENGER-RNA INHIBITS CENTRAL ANGIOTENSIN-INDUCED THIRST AND VASOPRESSIN

Antisense oligodeoxynucleotides (AS-ODN) to AT(1) receptor mRNA inhibit high blood pressure in Spontaneously Hypertensive Rats (SHR) when injected into the brain. The effect is presumably through inhibition of the actions of brain angiotensin II (Ang II). Central injection of Ang II elicits several physiological responses including release of vasopressin and motivation to drink. The angiotensin II type-I (AT(1)) receptor is located in brain regions which have been implicated in mediating these effects. Therefore we hypothesized that AS-ODN to AT(1) mRNA would inhibit the drinking and AVP response to central administration of Ang II in adult male SHR. AS-ODN were constructed to bases + 63 to + 77 (15-mer) of the AT(1) receptor RNA. 24 h after AS-ODN treatment (50 mu g/4 mu l) (intracerebroventricularly, i.c.v.), the drinking response to Ang II (50 ng, i.c.v.) was significantly reduced in the SHR (P<0.05). The drinking response to Ang II (i.c.v.) was also reduced in the Sprague-Dawley rats (P<0.05). There was no reduction of water intake in the control animals treated with scrambled ODN (SC-ODN). Repeated injection of AS-ODN did not produce a greater reduction in drinking response. Arginine vasopressin (AVP) release to central Ang II was significantly decreased after AS-ODN treatment when compared to vehicle (P<0.05) and to SC-ODN injections (P<0.05). Radioligand binding assays of the hypothalamic block after AS-ODN treatment showed a significant decrease of AT(1) receptor binding (P<0.05). The results show that the antisense inhibition of brain AT(1) receptor gene expression decreases the Ang II induced drinking and AVP release responses.