title: In vivo inhibition of angiotensin receptors in the rat kidney by candesartan cilexetil: a comparison with losartan.
abstract: The present study examined the in vivo effects of candesartan cilexetil compared with losartan on angiotensin II (Ang II) receptor binding in the rat kidney after oral administration. Male Sprague-Dawley rats (250 to 300 g) were gavaged with candesartan cilexetil or losartan in doses of 0.1, 0.3, 1, 3, 10, or 30 mg/kg, or corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood collected, and kidneys removed. The effects of candesartan cilexetil and losartan on Ang II receptor binding were determined by quantitative in vitro autoradiography using the radioligand [125I]-[Sar1,Ile8] Ang II. Ang II receptor binding in the kidney was mainly due to AT1 receptors with high levels of binding localized to the inner stripe of the outer medulla and glomeruli in cortical regions. Candesartan cilexetil (0.1 to 30 mg/kg) inhibited Ang II receptor binding to all anatomical sites of the kidney, in a dose-dependent manner. Losartan (0.1 to 30 mg/kg) also produced dose-dependent inhibition of Ang II receptor binding but was approximately 10- to 30-fold less potent than candesartan cilexetil. Inhibition of Ang II receptor binding was near maximal about 1 h after administration of candesartan cilexetil (10 mg/kg) or losartan (10 mg/kg), with both drugs producing persistent blockade at 24 h despite plasma renin activity and plasma drug concentrations returning to near normal levels. In vitro, candesartan, losartan, and EXP3174 (1 x 10(-10) to 1 x 10(-5) mol/L) displaced [125I]-[Sar1,Ile8] Ang II binding from AT1 receptors in the kidney in a concentration-dependent manner with a rank order of potency of candesartan > EXP3174 > losartan. The concentration required to displace 50% of radioligand binding (IC50) by candesartan, EXP3174, and losartan was 0.9+/-0.1 nmol/L, 3.4+/-0.4 nmol/L, and 8.9+/-1.1 nmol/L, respectively. In conclusion, the findings of the present study suggest that candesartan cilexetil is more potent than losartan in antagonizing AT1 receptors in the kidney in vivo. Nonetheless, both candesartan cilexetil and losartan produce rapid, complete, and sustained blockade of AT1 receptors in the rat kidney. Tissue blockade of Ang II receptors in target organs, such as the kidney, may contribute to the beneficial effects of Ang II receptor antagonists as antihypertensive agents.
authors.affiliation: Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, VIC, Australia. m.fabiani@austin.unimelb.edu.au
authors.forename: M E
authors.initials: ME
authors.lastname: Fabiani
authors.forename: D T
authors.initials: DT
authors.lastname: Dinh
authors.forename: L
authors.initials: L
authors.lastname: Nassis
authors.forename: D J
authors.initials: DJ
authors.lastname: Casley
authors.forename: C I
authors.initials: CI
authors.lastname: Johnston
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000097:blood / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000097:blood / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D019808:Losartan / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000378:metabolism; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000378:metabolism
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D012083:Renin; C066026:losartan carboxylic acid; D019808:Losartan; C077793:candesartan cilexetil