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 micrograms 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 AT1 receptor mRNA also produced a long-lasting decrease in blood pressure in SHR (7 days). After AS-ODN treatment AT1 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.