Effects of antisense oligodeoxynucleotide targeting of the α2B-adrenergic receptor messenger RNA in the central nervous system

Abstract

The results of previous studies with genetically engineered mice have suggested that an intact central α2B-adrenergic receptor (α2B-AR) subtype mediates the development and maintenance of salt-induced hypertension. In the present study, we sought to further define the role of this receptor by injecting antisense oligodeoxynucleotides (AS-ODNs), targeting a selected sequence of the α2B-AR mRNA, into the lateral cerebral ventricle of rats that had undergone prior subtotal nephrectomy and dietary salt loading. Cell culture studies showed that these AS-ODNs could block α2B-AR protein generation. Before AS-ODN injection, blood pressure (BP) averaged 133 ± 5 mm Hg during the daytime and rose to 165 ± 4 mm Hg during the nighttime activity hours (P<0.001 versus baseline average of 120 ± 2 mm Hg). The injection of AS-ODNs during the early afternoon prevented the BP rise and was associated with a significant fall in heart rate (from 385 ± 12 to 306 ± 15 bpm, P