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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216

Submitted 1 March 2004 ; accepted in final form 17 May 2004

We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31–50; RNASTAAS2, position 21–40; RNASTAAS3, position 143–162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 µg/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 ± 6 mmHg (after SCR2) to 106 ± 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, –31 mmHg; RNASTAAS3, –16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (–15 to –41 mmHg) was comparable to the effects of captopril (100 mg·kg^–1·day^–1 for 3 days: –32 mmHg) and an AT₁ receptor antagonist (L-158809, 1.5 mg·kg^–1·day^–1 for 3 days: –36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR.

renin-angiotensin system; ribonucleic acid half-life; mean arterial pressure; plasma renin activity

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