title: Effects of losartan on vasoconstrictor responses to angiotensin II in the forearm vascular bed of healthy volunteers.
abstract: OBJECTIVE
  The angiotensin type 1 (AT1) receptor antagonist, losartan (orally administered), decreases vasoconstrictor effects of angiotensin II (Ang II). Oral losartan is converted into the active metabolite, Exp3174, which causes most of the antagonistic effects. Effects of losartan as such have not been studied after its intra-arterial administration in humans. Therefore, we investigated the effects of both intra-arterially and orally administered losartan on AT1-receptor-mediated vasoconstriction.
  
  
  METHODS
  Forearm vascular resistance (FVR) was determined by venous occlusion plethysmography in 24 healthy subjects. Ang II (0.01, 0.1, 1.0, and 10.0 ng/kg/min) was infused into the brachial artery, before and after losartan, administered intra-arterially (dose range 100-3000 ng/kg/min) or orally (50 mg once daily for 5 days).
  
  
  RESULTS
  Ang II concentration-dependently increased FVR (P < 0.05); tachyphylaxis did not occur. Losartan alone did not change FVR. Intra-arterially infused losartan dose-dependently inhibited Ang-II-induced vasoconstriction. At a concentration of 10(-8) M Ang II, losartan reduced FVR, as a percentage of baseline values, from 287 +/- 30 to 33 +/- 8% (mean +/- s.e.m.; P < 0.05). Orally given losartan reduced FVR from 297 +/- 40 to 73 +/- 19% (P < 0.05).
  
  
  CONCLUSIONS
  Losartan, intra-arterially administered, causes no effect on baseline vascular resistance, but markedly inhibits Ang-II-induced vasoconstriction in the human forearm vascular bed. Relatively high doses of intra-arterial losartan were required when compared to the antagonism by the orally administered drug. These data indicate that Ang-II-induced vasoconstriction is mediated by AT1-receptors, which are blocked by losartan. The more effective antagonism exerted by oral losartan is presumably explained by the formation of Exp3174. Endogenous Ang II does not contribute to baseline vascular tone in healthy, sodium-replete, subjects.
authors.affiliation: Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Baan
authors.forename: P C
authors.initials: PC
authors.lastname: Chang
authors.forename: P
authors.initials: P
authors.lastname: Vermeij
authors.forename: M
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: P A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D019808:Losartan; D008297:Male; D010991:Plethysmography; D013777:Tetrazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan