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Elevated blood pressure in normotensive rats produced by ‘knockdown’ of the angiotensin type 2 receptor
Author(s) -
Wang HongWei,
Gallinat Stefan,
Li Hongwei,
Sumners Colin,
Raizada Mohan K.,
Katovich Michael J.
Publication year - 2004
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2004.027359
Subject(s) - medicine , endocrinology , angiotensin ii , gene knockdown , receptor , renin–angiotensin system , in vivo , transgene , angiotensin receptor , blood pressure , angiotensin ii receptor type 1 , biology , chemistry , gene , biochemistry , microbiology and biotechnology
Most of our knowledge of the function of the angiotensin type 2 receptor (AT 2 R) has been obtained from transgenic mouse models. The aim of the present study was to investigate the role of the AT 2 R in normotensive Sprague–Dawley (SD) rats by using antisense gene transfer technology to ‘knockdown’ this specific receptor subtype. A retroviral vector containing full‐length AT 2 R antisense cDNA (AT 2 R‐AS) was constructed and the effectiveness of the transduction of AT 2 R‐AS was studied in vitro . In subsequent in vivo studies, 5‐day‐old normotensive SD rats received a single intracardiac bolus (25 μl) of AT 2 R‐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 AT 2 R‐AS transcript and a reduction in mRNA and binding of the AT 2 R was observed in vitro . Expression of AT 2 R‐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 AT 2 R‐AS‐treated rats. However, AT 2 R‐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 AT 2 receptors in rats results in similar cardiovascular and dipsogenic responses as reported in AT 2 R knockout mice. The actions of the AT 2 receptors appear to be antagonistic to the cardiovascular actions of the AT 1 receptors, whereas AT 1 and AT 2 receptors appear to act synergistically in the regulation of water intake.