ANTISENSE INHIBITION OF HYPERTENSION - A NEW STRATEGY FOR RENIN-ANGIOTENSIN CANDIDATE GENES

Antisense inhibition of hypertension: A new strategy for renin-angiote nsin candidate genes. There are several ways of experimentally studyin g the influence of candidate genes on hypertension. The approach propo sed here is antisense inhibition with antisense oligodeoxynucleotides (AS-ODNs) constructed to the 5' region of known sequences of angiotens inogen mRNA and angiotensin II type-1 receptor mRNA. The AS-ODNs were applied in vivo and in vitro. In vivo, direct injection of 50 mu g of AS-ODN into the lateral ventricles of SHR reduced hypertension signifi cantly (P < 0.01). There was no effect of AS-ODN i.c.v. in normotensiv e WKY rats. The phosphorothiated AS-ODN to the AT(1) receptor mRNA als o produced a long-lasting decrease in blood pressure in SHR (7 days). After AS-ODN treatment AT, receptors were reduced in the PVN and anter ior third ventricle area and Ang II levels were reduced in the brainst em. The results show the in vivo feasibility of using antisense inhibi tion of renin-angiotensin mRNA to reduce hypertension.