Angiotensin II AT1A receptor antisense lowers blood pressure in acute 2-kidney, 1-clip hypertension

To test the effectiveness of antisense oligonucleotides targeted to the angiotensin type 1A (AT(1A)) receptor mRNA on blood pressure reduction, the 2-kidney, 1-clip (2K1C) Goldblatt model of hypertension was studied in the acute phase of hypertension, when the peripheral renin-angiotensin system is overactive. A single injection of AT(1A) receptor antisense oligodeoxynucleotides significantly reduced systolic blood pressure for a period of 8 days in 2K1C rats after clipping, from 157.5 +/-5 mm Hg on day 7 to 141.3 +/-3.0 mm Hg on day 15 after clipping (P <0.01). The AT(1A) receptor antisense oligonucleotide labeled with fluorescein shows that the antisense oligonucleotide at 24 hours was taken up into aorta, mesenteric artery, liver, kidney glomeruli, and medulla, remaining up to 6 days. The AT(1A) receptor number in fmol/g tissue was significantly decreased after AT(1A) receptor antisense oligonucleotide treatment in the dorsal aorta, mesenteric artery, renal cortex, and renal medulla (P <0.05) compared with that of the AT(1A) receptor-scrambled antisense oligonucleotide control-treated group. The data clearly demonstrate a prolonged antihypertensive effect of AT(1A) receptor antisense oligonucleotide in the 2K1C renovascular model of hypertension when it is administered intravenously in a single low dose (0.33 mg/kg(-1)). It also shows that the AT(1A) receptor antisense oligonuclcotide is actively taken up by AT(1A) target tissues and that there is a significant decrease in receptor density. We conclude that in the acute phase of 2K1C hypertension, antisense to AT(1A) receptor decreases AT(1A) receptor density, which attenuates the vascular vasoconstrictive effects of high plasma angiotensin II levels and in the kidney elicits natriuresis. The decrease in renal AT(1A) receptor density may also lead to sodium loss and reduction of extracellular volume.