ANTISENSE INHIBITION OF AT(1) RECEPTOR MESSENGER-RNA AND ANGIOTENSINOGEN MESSENGER-RNA IN THE BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS REDUCES HYPERTENSION OF NEUROGENIC ORIGIN
R. Gyurko et al., ANTISENSE INHIBITION OF AT(1) RECEPTOR MESSENGER-RNA AND ANGIOTENSINOGEN MESSENGER-RNA IN THE BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS REDUCES HYPERTENSION OF NEUROGENIC ORIGIN, Regulatory peptides, 49(2), 1993, pp. 167-174
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 (OD
Ns), intracerebroventricularly (i.c.v). Antisense ODNs were constructe
d 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 antise
nse ODNs to normotensive levels. The phosphorothioated antisense ODN t
o the AT(1) receptor produced long-lasting (7 days) decreases in blood
pressure. After AT(1) antisense treatment, AT(1) receptors were reduc
ed in the paraventricular nucleus (PVN) and in the anterior third vent
ricle area (AV3V). Following angiotensinogen antisense treatment, angi
otensin II levels were significantly reduced in the brainstem (P<0.05)
, indicating arrest of angiotensin II synthesis. The results demonstra
te that inhibiting the brain renin-angiotensin system by antisense inh
ibition of the angiotensinogen and the AT(1) receptor genes, lowers hi
gh blood pressure in the SHR. The antisense administration to specific
genes of the tissue renin-angiotensin system offers the possibility o
f a new approach to developing antihypertension treatments.