A DECREASE IN ANGIOTENSIN RECEPTOR-BINDING IN RAT-BRAIN NUCLEI BY ANTISENSE OLIGONUCLEOTIDES TO THE ANGIOTENSIN AT(1) RECEPTOR

Intracerebroventricular (i.c.v.) injections of antisense oligonucleoti des against mRNA of the angiotensin type 1 (AT(1)) receptor have been shown to reduce blood pressure in spontaneously hypertensive (SHR) rat s and angiotensin II-induced drinking in both SHR and Sprague-Dawley ( SD) rats. The present investigation was designed to quantify the effec t of i.c.v. injections of antisense oligonucleotides to the AT(1) rece ptor mRNA on brain angiotensin receptors using membrane binding and au toradiographic analysis. Control injections contained sense or scrambl ed oligonucleotides or saline. Three daily injections of antisense oli gonucleotides into the third ventricle of SD rats decreased the AT(1) receptor number significantly by 25% in a hypothalamic tissue block. A T(2) receptors were not altered. Autoradiography showed a decrease in angiotensin receptor number in hypothalamic nuclei and in the anterove ntral region of the third ventricle (AV3V) after antisense treatment. AT(2) receptors were not reduced indicating the AT(1) antisense oligon ucleotides were specific. In a second series of experiments, single in jections of antisense oligonucleotides into the lateral ventricle of S HR rats were tested. Antisense oligonucleotides produced a significant decrease in receptor number in the same hypothalamic area. Sense and scrambled oligonucleotides did not decrease the receptor numbers signi ficantly. The decreases observed after injection of antisense oligonuc leotides were between 15 and 30%. These changes may be sufficient to a ccount for the physiological effects of i.c.v. injections of antisense oligonucleotides to AT(1) receptor mRNA.