title: Comparative vascular and renal tubular effects of angiotensin II receptor blockers combined with a thiazide diuretic in humans.
abstract: OBJECTIVE
  The goal of this study was to investigate whether angiotensin II receptor blockers (ARBs) induce a comparable blockade of AT1 receptors in the vasculature and in the kidney when the renin-angiotensin system is activated by a thiazide diuretic.
  
  
  METHODS
  Thirty individuals participated in this randomized, controlled, single-blind study. The blood pressure and renal hemodynamic and tubular responses to a 1-h infusion of exogenous angiotensin II (Ang II 3 ng/kg per min) were investigated before and 24 h after a 7-day administration of either irbesartan 300 mg alone or in association with 12.5 or 25 mg hydrochlorothiazide (HCTZ). Irbesartan 300/25 mg was also compared with losartan 100 mg, valsartan 160 mg, and olmesartan 20 mg all in association with 25 mg HCTZ. Each participant received two treatments with a 1-week washout period between treatments.
  
  
  RESULTS
  The blood pressure response to Ang II was blocked by more than 90% with irbesartan alone or in association with HCTZ and with olmesartan/HCTZ and by nearly 60% with valsartan/HCTZ and losartan/HCTZ (P < 0.05). In the kidney, Ang II reduced renal plasma flow by 36% at baseline (P < 0.001). Irbesartan +/- HCTZ and olmesartan/HCTZ blocked the renal hemodynamic response to Ang II nearly completely, whereas valsartan/HCTZ and losartan/HCTZ only blunted this effect by 34 and 45%, respectively. At the tubular level, Ang II significantly reduced urinary volume (-84%) and urinary sodium excretion (-65%) (P < 0.01). These tubular effects of Ang II were only partially blunted by the administration of ARBs.
  
  
  CONCLUSIONS
  These data demonstrate that ARBs prescribed at their recommended doses do not block renal tubular AT1 receptors as effectively as vascular receptors do. This observation may account for the need of higher doses of ARB for renal protection. Moreover, our results confirm that there are significant differences between ARBs in their capacity to induce a sustained vascular and tubular blockade of Ang II receptors.
authors.affiliation: Service of Nephrology and Hypertension Consultation, Department of Medicine, CHUV, Lausanne, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Coltamai
authors.forename: Marc
authors.initials: M
authors.lastname: Maillard
authors.forename: Alexandra
authors.initials: A
authors.lastname: Simon
authors.forename: Bruno
authors.initials: B
authors.lastname: Vogt
authors.forename: Michel
authors.initials: M
authors.lastname: Burnier
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D000077405:Irbesartan; D007684:Kidney Tubules / Q000187:drug effects*; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D016037:Single-Blind Method; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004232:Diuretics; D007093:Imidazoles; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000068756:Valsartan; C437965:olmesartan; D014633:Valine; D000077405:Irbesartan; D019808:Losartan