INHIBITION OF HYPERTENSION BY PERIPHERAL ADMINISTRATION OF ANTISENSE OLIGODEOXYNUCLEOTIDES

We administered liposome-encapsulated antisense oligodeoxynucleotide t argeted to angiotensinogen mRNA peripherally to spontaneously hyperten sive rats to test whether peripheral angiotensinogen reduction would l ower their hypertensive blood pressures and to determine the role of p eripheral angiotensinogen in the modulation of hypertension. Using in vitro translation techniques, we tested the sequence specificity of th e antisense sequence. The selected antisense sequence decreased angiot ensinogen production in vitro, enabling us to distinguish between spec ific and nonspecific effects. To increase the efficiency of peripheral and hepatic antisense delivery, oligonucleotides were liposome encaps ulated for intra-arterial administration. Confocal microscopy was used for determination of the hepatic distribution of fluorescently labele d antisense. Encapsulated antisense molecules were seen to be distribu ted within liver tissue 1 hour after injection; however, little or no uptake was observed with the unencapsulated oligonucleotides. We also determined the physiological effects of antisense oligodeoxynucleotide targeted to liver angiotensinogen mRNA. Administration of liposome-en capsulated antisense significantly decreased hypertensive blood pressu res to normotensive levels compared with scrambled control oligonucleo tides, unencapsulated antisense, and empty liposomes (P=.013). These d ata were supported by biochemical changes elicited by the antisense tr eatment. Rats receiving liposome-encapsulated antisense had significan tly lowered peripheral angiotensinogen and angiotensin IT levels compa red with control groups (P<.05). No significant heart rate changes wer e observed in the antisense or control groups. These results suggest t hat peripheral angiotensinogen plays a role in the maintenance of hype rtensive blood pressure in this model of hypertension and that periphe ral administration of antisense molecules is possible with organ-targe ted delivery mechanisms.