Meng H, Wielbo D, Gyurko R, Phillips M I
Department of Physiology, College of Medicine, University of Florida, Gainesville 32610, USA.
Regul Pept. 1994 Dec 15;54(2-3):543-51. doi: 10.1016/0167-0115(94)90551-7.
Antisense oligodeoxynucleotides (AS-ODN) to AT1 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 (AT1) receptor is located in brain regions which have been implicated in mediating these effects. Therefore we hypothesized that AS-ODN to AT1 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 AT1 receptor RNA. 24 h after AS-ODN treatment (50 micrograms/4 microliters) (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 AT1 receptor binding (P < 0.05). The results show that the antisense inhibition of brain AT1 receptor gene expression decreases the Ang II induced drinking and AVP release responses.
将针对AT1受体mRNA的反义寡脱氧核苷酸（AS - ODN）注入自发性高血压大鼠（SHR）脑内可降低其血压。该效应可能是通过抑制脑内血管紧张素II（Ang II）的作用实现的。脑室内注射Ang II会引发多种生理反应，包括抗利尿激素释放和饮水动机。血管紧张素II 1型（AT1）受体位于与介导这些效应相关的脑区。因此，我们推测针对AT1 mRNA的AS - ODN会抑制成年雄性SHR对脑室内注射Ang II的饮水和抗利尿激素反应。AS - ODN构建针对AT1受体RNA的+63至+77碱基（15聚体）。AS - ODN处理（50微克/4微升，脑室内注射，i.c.v.）24小时后，SHR对Ang II（50纳克，脑室内注射）的饮水反应显著降低（P < 0.05）。Sprague - Dawley大鼠对脑室内注射Ang II的饮水反应也降低了（P < 0.05）。用乱序ODN（SC - ODN）处理的对照动物饮水量没有减少。重复注射AS - ODN并未使饮水反应进一步显著降低。与溶剂对照组相比（P < 0.05）以及与SC - ODN注射组相比（P < 0.05），AS - ODN处理后，脑室内注射Ang II引起的精氨酸血管加压素（AVP）释放显著减少。AS - ODN处理后下丘脑区的放射性配体结合试验显示AT1受体结合显著减少（P < 0.05）。结果表明，脑内AT1受体基因表达的反义抑制降低了Ang II诱导的饮水和AVP释放反应。
