In vivo effects of partial phosphorothioated AT(1) receptor antisense oligonucleotides in spontaneously hypertensive and normotensive rats

Partial phosphorothioate (PS) antisense oligodeoxynucleotides (ODNs) target ed against rat AT(1) receptor mRNA have been used to control blood pressure in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Molecules were injected intracerebroventricularly (i.c.v., right lateral ventricle) in freely moving animals. The antisense ODN lowered the mean arterial press ure (MAP) 24 hours (-43 mmHg+/-10) and 48 hours (-30 mmHg+/-13) after injec tion, while the control ODN molecule had no significant effects. The observ ed decrease of blood pressure was due to a specific inhibition of AT(1) rec eptor gene expression, since the level of its mRNA, monitored by reverse tr anscription (RT)- polymerase chain reaction (PCR), was significantly reduce d by antisense molecule (-40%), compared to sense one. in normotensive rats no effect on MAP have been observed, while AT(1) receptor gene expression is reduced (-40%) by antisense treatment. It is known that SHRs have an enh anced basal activity of the central renin-angiotensin system that induces a n increase in central sympathetic outflow. instead in WKY rats the central sympathetic outflow is not conditioned by the enhanced activity of brain re nin-angiotensin system. Therefore in normotensive rats although partial PS ODN reduces the AT(1) mRNA level this will not result in a modification of the sympathetic outflow and no change in MAP level would be observed.