Antisense inhibition of hypertension: a new strategy for renin-angiotensin candidate genes.

There are several ways of experimentally studying the influence of candidate genes on hypertension (HT). The approach proposed here is antisense inhibition with antisense oligodeoxynucleotides (AS-ODNs) constructed to the 5′ region of known sequences of angiotensinogen (AGT) mRNA and angiotensin II type-1 receptor (AT1-R) mRNA. In vivo direct injection of 50 μg of AS-ODN into the lateral ventricles of SHR reduced HT significantly (p<0.01). There was no effect of AS-ODN i.c.v. in normotensive WKY rats at the dose used. The phosphorothiated AS-ODN to the AT1-R mRNA also produced a long-lasting decrease in blood pressure in SHR (7 days). After AS-ODN treatment, AT1-R were reduced in the PVN and anterior third ventricle area and Ang II levels were reduced in the brainstem. To test a different model of hypertension we applied AS-ODN to AGT mRNA in 2K-1C hypertensive rats. Rats were clipped 6 months prior to testing to produce chronic phase renovascular HT. At this stage, plasma renin is normal and we hypothesized that brain Ang II maintains the HT through sympathetic hyperactivation. AS-ODN directed to AGT mRNA i.c.v. significantly reduced BP (p<0.05). There was no effect with the vehicle or sense ODN control. Hypothalamic Ang II levels were reduced by the AS-ODN and plasma epinephrine was significantly reduced. We conclude that antisense inhibition offers a new approach to reducing HT through sequence specific translation inhibition of overactive genes.