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(Hypertension. 2001;38:1075.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Effects of Antisense Oligodeoxynucleotide Targeting of the _2B-Adrenergic Receptor Messenger RNA in the Central Nervous System

Ekaterina Kintsurashvili; Irene Gavras; Conrado Johns; Haralambos Gavras

From the Hypertension and Atherosclerosis Section, Department of Medicine, Boston University School of Medicine, Boston, Mass.

Correspondence to Haralambos Gavras, MD, Chief, Hypertension & Atherosclerosis Section, Boston University School of Medicine, 715 Albany St, Boston, MA 02118. E-mail hgavras{at}bu.edu

Abstract—— The results of previous studies with genetically engineered mice have suggested that an intact central _2B-adrenergic receptor (_2B-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 _2B-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 _2B-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<0.05) and symptoms of sedation that lasted for several hours, with a peak at 3 to 6 hours and full recovery by 24 hours. At that time, a second injection produced identical effects in all rats (n=9). Control rats (n=10) that received scrambled ODN injections had no changes in BP or heart rate patterns, and neither group had evidence of neurotoxicity, indicating that these effects are specifically due to translational inhibition of central _2B-AR. We conclude that a fully functional central _2B-AR is necessary for the induction of salt-dependent hypertension.

Key Words: hypertension, sodium dependent • genes • antihypertensive therapy

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