ANTISENSE INHIBITION OF HYPERTENSION IN THE SPONTANEOUSLY HYPERTENSIVE RAT

Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to a ngiotensinogen mRNA was administered intracerebroventricularly in spon taneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hyper tensive blood pressures to normotensive levels in spontaneously hypert ensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered bl ood pressure. Injections of ASODN at the same dose that decreased hype rtension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensin ogen production was decreased in the brain stem and significantly decr eased in the hypothalamus of the ASODN-treated rats (P<.05), supportin g the concept of centrally mediated regulation of hypertension by an o veractive brain angiotensin system. To determine the distribution of c entrally administered oligodeoxynucleotides, fluorescein isothiocyanat e-conjugated oligodeoxynucleotides were injected directly into the lat eral ventricles. One hour later, oligodeoxynucleotides were distribute d throughout the lateral and third ventricles, with tissue and cellula r uptake observed in discrete cells at the injection site. This indica tes that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and s how that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the sponta neously hypertensive rat through a central mechanism.