title: Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.
abstract: The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.
authors.affiliation: Department of Medicine, University of Virginia Health System, Charlottesville 22908, USA. rmc4c@virginia.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Carey
authors.forename: N L
authors.initials: NL
authors.lastname: Howell
authors.forename: X H
authors.initials: XH
authors.lastname: Jin
authors.forename: H M
authors.initials: HM
authors.lastname: Siragy
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001795:Blood Pressure Determination; D004039:Diet, Sodium-Restricted; D007022:Hypotension / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068756:Valsartan; D014664:Vasodilation / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C060894:CGP 42112A; D009569:Nitric Oxide; D000068756:Valsartan; D019001:Nitric Oxide Synthase; D014633:Valine; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester