This proposal will continue to elucidate the role of the tissue renin-angiotensin system (RAS) in hypertension. Work in the previous proposal has established physiological, cellular and molecular functions of tissue RAS, particularly in the brain. The hypothesis of this application is that an overactive brain RAS contributes to the development and maintenance of hypertension. To test this hypothesis the investigator proposes to use antisense inhibition of angiotensinogen mRNA and angiotensin type-1 receptor (AT1) mRNA in spontaneously hypertensive and renovascular hypertensive rats.
The first aim i s to expand their recent findings showing a substantial decrease in hypertension with antisense inhibition using modified oligodeoxynucleotides to prolong the effect.
The second aim i s to test the mechanisms of antisense inhibition on the tissue RAS by showing that angiotensinogen levels and AT1 receptor binding sites have been decreased. Uptake and stability of oligos will be studied in vivo and in vitro.
The third aim i s to develop a gene delivery system for long-term inhibition with antisense incorporated in an adeno-associated virus (AAV) expression vector.
The fourth aim will be to test the AAV vector in vivo, first in adult rats with hypertension to test if the anti- hypertensive effect can be prolonged, and second in young 4-6 week old SHR before hypertension develops to test if hypertension can be prevented from developing by early inhibition of brain RAS. The fifth aim will test the oligodeoxynucleotides in the 2K1C model of hyper- tension in the acute, intermediate and chronic phase.
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