Antisense inhibition of angiotensinogen attenuates vasopressin release in the paraventricular hypothalamic nucleus of spontaneously hypertensive rats

It has been reported that intracerebroventricularly injected antisense oligonucleotide to angiotensinogen reduces arterial pressure in spontaneously hypertensive rats (SHR), but the mechanism and the sites of action remain unclear. In the present study, we examined whether injection of antisense oligonucleotide to angiotensinogen into the paraventricular hypothalamic nucleus (PVN) would influence arterial pressure and vasopressin release. For this purpose, 12-week-old male SHR were cannulated into the bilateral PVN. One week later, we injected antisense or sense oligonucleotide to angiotensinogen into the bilateral PVN (0.2 nmol/200 nl each side). After 24 h, we directly monitored arterial pressure, and then took blood samples to measure plasma vasopressin, catecholamines and renin activity. Mean arterial pressure did not change in either group (from 144 +/- 3 to 154 +/- 4 mmHg for the antisense oligonucleotide group, n = 11; from 147 +/- 4 to 156 +/- 3 mmHg for the sense oligonucleotide group, n = 11). Antisense oligonucleotide attenuated vasopressin release compared with sense oligonucleotide (1.30 +/- 0.28 vs. 3.29 +/- 0.60 pg/ml, respectively, P < 0.01). Plasma catecholamines also decreased in the antisense oligonucleotide group compared with the sense oligonucleotide group. However, the plasma renin activity did not differ between the groups. In the additional experiment, we examined the neurohormonal and cardiovascular effects of intracerebroventricularly injected antisense oligonucleotide to angiotensinogen in SHR. Mean arterial pressure, plasma vasopressin and plasma norepinephrine were significantly lower in the antisense oligonucleotide group than in the sense oligonucleotide group. These results suggest that angiotensinogen in PVN plays important roles in vasopressin release and sympathetic nerve activity, but may not contribute to the maintenance of arterial pressure in SHR. (C) 1999 Elsevier Science B.V. All rights reserved.