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1 Department of Physiology and Functional Genomics, College of Medicine2 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Most of our knowledge of the function of the angiotensin type 2 receptor (AT2R) has been obtained from transgenic mouse models. The aim of the present study was to investigate the role of the AT2R in normotensive Sprague–Dawley (SD) rats by using antisense gene transfer technology to ‘knockdown’ this specific receptor subtype. A retroviral vector containing full-length AT2R antisense cDNA (AT2R-AS) was constructed and the effectiveness of the transduction of AT2R-AS was studied in vitro. In subsequent in vivo studies, 5-day-old normotensive SD rats received a single intracardiac bolus (25 µl) of AT2R-AS viral particles. When animals reached adulthood, direct blood pressure (BP), and both pressor and dipsogenic responses to angiotensin II were investigated. Long-lasting expression of the AT2R-AS transcript and a reduction in mRNA and binding of the AT2R was observed in vitro. Expression of AT2R-AS transcript was maintained for 90 days in heart, kidney, lung and brain, indicating a high degree of transgene transduction in vivo. As adults, systolic BP and the pressor responses to angiotensin were significantly elevated in AT2R-AS-treated rats. However, AT2R-AS-treated rats displayed significantly reduced dipsogenic responses to both angiotensin and water deprivation. Collectively, these data demonstrate that a single neonatal injection of the retroviral vector containing antisense to the AT2 receptors in rats results in similar cardiovascular and dipsogenic responses as reported in AT2R knockout mice. The actions of the AT2 receptors appear to be antagonistic to the cardiovascular actions of the AT1 receptors, whereas AT1 and AT2 receptors appear to act synergistically in the regulation of water intake.
(Received 23 January 2004;
accepted after revision 4 March 2004; first published online 16 March 2004)
Corresponding author M. J. Katovich: College of Pharmacy, Box 100487 JHMHC, University of Florida, Gainesville, FL 32610, USA. Email: TUkatovich{at}cop.ufl.edu
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