Hb. Meng et al., ANTISENSE OLIGONUCLEOTIDE TO AT(1) RECEPTOR MESSENGER-RNA INHIBITS CENTRAL ANGIOTENSIN-INDUCED THIRST AND VASOPRESSIN, Regulatory peptides, 54(2-3), 1994, pp. 543-551
Antisense oligodeoxynucleotides (AS-ODN) to AT(1) receptor mRNA inhibi
t high blood pressure in Spontaneously Hypertensive Rats (SHR) when in
jected 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 vasop
ressin and motivation to drink. The angiotensin II type-I (AT(1)) rece
ptor is located in brain regions which have been implicated in mediati
ng 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 resp
onse 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 t
he Sprague-Dawley rats (P<0.05). There was no reduction of water intak
e in the control animals treated with scrambled ODN (SC-ODN). Repeated
injection of AS-ODN did not produce a greater reduction in drinking r
esponse. Arginine vasopressin (AVP) release to central Ang II was sign
ificantly decreased after AS-ODN treatment when compared to vehicle (P
<0.05) and to SC-ODN injections (P<0.05). Radioligand binding assays o
f the hypothalamic block after AS-ODN treatment showed a significant d
ecrease 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.