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

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. The approach proposed here is antisense inhibition with antisense oligodeoxynucleotides (AS-ODNs) constructed to the 5' region of known sequences of angiotensinogen 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 significantly (P < 0.01). There was no effect of AS-ODN i.c.v. in normotensive WKY rats. The phosphorothiated AS-ODN to the AT(1) receptor mRNA also produced a long-lasting decrease in blood pressure in SHR (7 days). After AS-ODN treatment AT, receptors were reduced in the PVN and anterior third ventricle area and Ang II levels were reduced in the brainstem. The results show the in vivo feasibility of using antisense inhibition of renin-angiotensin mRNA to reduce hypertension.