title: Differences in AT2 -receptor stimulation between AT1 -receptor blockers valsartan and losartan quantified by renal interstitial fluid cGMP.
abstract: OBJECTIVE
  Angiotensin II-receptor blockers are an established class of antihypertensive agents, but the differences between individual members of the class are largely unknown. The present study employed an animal model to demonstrate angiotensin II-receptor blocker-specific effects and to quantify these differences by comparing two common agents, losartan and valsartan.
  
  
  METHODS
  We measured the effects on angiotensin II AT2-receptor-mediated renal cGMP by microdialysis in the outer renal cortex in conscious normotensive, sodium-depleted, 4-week-old Sprague-Dawley rats. Rats (n = 8) were given equimolar and equidepressor doses of losartan (0.02 mmol/kg) or valsartan (0.02 mmol/kg) either intravenously or orally. Time was allowed for the conversion of losartan into its active metabolite, EXP 3174.
  
  
  RESULTS
  Both drugs had equal effects on blood pressure. There were significantly greater increases in cGMP levels after administration of valsartan than of losartan with both routes of administration. Intravenous administration of valsartan led to a 69.1% increase in cGMP, versus a 10.3% increase with losartan. Five hours after oral administration of valsartan, a 48% increase in cGMP was observed versus a 10.9% increase with losartan. The increase after oral administration of valsartan was sustained 8 h after administration, whereas the effect of losartan was not sustained. The effects of losartan and valsartan on cGMP were completely inhibited by AT2-receptor blockade.
  
  
  CONCLUSIONS
  The results indicate that AT1-receptor blockade with valsartan influences AT2-receptor-mediated angiotensin II responses to a greater extent than with losartan, as quantified by renal interstitial fluid cGMP.
authors.affiliation: Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA. hms7a@virginia.edu
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: El-Kersh
authors.forename: Marc
authors.initials: M
authors.lastname: De Gasparo
authors.forename: Randy L
authors.initials: RL
authors.lastname: Webb
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D006152:Cyclic GMP; D014633:Valine; D019808:Losartan