ANTISENSE INHIBITION OF AT(1) RECEPTOR MESSENGER-RNA AND ANGIOTENSINOGEN MESSENGER-RNA IN THE BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS REDUCES HYPERTENSION OF NEUROGENIC ORIGIN

To determine the role of angiotensinogen and angiotensin II type-i (AT(1),) receptor genes in hypertension, spontaneously hypertensive rats (SHR) were injected with synthetic antisense oligodeoxynucleotides (ODNs), intracerebroventricularly (i.c.v). Antisense ODNs were constructed to bases -5 to +13 of angiotensinogen mRNA (18-mer) and to bases +63 to +77 (15-mer) of angiotensin II type-1 receptor mRNA. Hypertension was significantly reduced by the application of 50 mu g of both antisense ODNs to normotensive levels. The phosphorothioated antisense ODN to the AT(1) receptor produced long-lasting (7 days) decreases in blood pressure. After AT(1) antisense treatment, AT(1) receptors were reduced in the paraventricular nucleus (PVN) and in the anterior third ventricle area (AV3V). Following angiotensinogen antisense treatment, angiotensin II levels were significantly reduced in the brainstem (P<0.05), indicating arrest of angiotensin II synthesis. The results demonstrate that inhibiting the brain renin-angiotensin system by antisense inhibition of the angiotensinogen and the AT(1) receptor genes, lowers high blood pressure in the SHR. The antisense administration to specific genes of the tissue renin-angiotensin system offers the possibility of a new approach to developing antihypertension treatments.