title: Angiotensin II type 1 (AT-1) receptor inhibition partially prevents the urodynamic and detrusor changes associated with bladder outlet obstruction: a mouse model.
abstract: Study Type - Therapy (case control) Level of Evidence 3b What's known on the subject? and What does the study add? Angiotensin II is the main effector peptide in the bladder local renin-angiotensin system. This experiment demonstrates the role of this local renin-angiotensin system with respect to bladder outlet obstruction.
  
  
  OBJECTIVE
  • To determine if treatment with an angiotensin II type 1 (AT-1) receptor antagonist, losartan, can prevent the structural and functional changes that occur in a mouse model of bladder outlet obstruction (BOO).
  
  
  METHODS
  • Twenty-four Balb/CAN mice underwent partial urethral obstruction for 6 weeks. • Twelve mice were given oral losartan (10 mg/kg/day), and 12 were not. Six mice served as unobstructed controls, and six unobstructed mice were given oral losartan (10 mg/kg/day) to determine the effect of angiotensin II inhibition on the normal bladder. • Bladder capacity (C), detrusor pressure during voiding (Pdet) and volume at first non-voiding contraction (NVC1) as a percentage of C were recorded after 6 weeks. • Bladders were stained with haematoxylin and eosin for measurement of detrusor muscular thickness, and graded as 1 = atrophy (<100 µm thick), 2 = normal (100-200 µm thick), 3 = hypertrophy (>200 µm thick) compared with controls.
  
  
  RESULTS
  • Compared with controls, BOO mice had greater C (153.5 ± 20.9 vs 57.5 ± 7.4 µl, P < 0.01), higher Pdet (28.8 ± 2.1 vs 12.1 ± 2.1 mm Hg), lower NVC1 (median = 24% vs 54% P= 0.03). BOO mice manifested greater bladder weight (93.2 ± 11.7 mg vs 26.8 ± 2.40 mg, P < 0.01) and greater detrusor muscle thickness (median 3 vs 2, P= 0.02). • Compared with untreated BOO mice, mice treated with losartan had greater mean C (248.8 ± 28.6 vs 153.5 ± 20.9 µL, P= 0.01), no significant change in mean Pdet (24.7 ± 1.6 vs 28.8 ± 2.1 mm Hg, P= 0.2) and a higher mean NVC1 (47% vs 24%, P= 0.02). • Treatment with losartan mediated an insignificant reduction in mean bladder weight (68.1 ± 9.1 mg vs 93.2 ± 11.7 mg, P= 0.10), but a significant reduction in detrusor muscle thickness (median 2 vs 3, P= 0.02). Losartan did not mediate any significant structural or functional changes in the unobstructed mouse bladder.
  
  
  CONCLUSIONS
  • In a mouse model of BOO, treatment with an AT-1 antagonist partially prevented the urodynamic and structural changes that otherwise occur with BOO.
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, CA, USA. ccomiter@stanford.edu
authors.forename: Craig
authors.initials: C
authors.lastname: Comiter
authors.forename: Hardeep S
authors.initials: HS
authors.lastname: Phull
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008026:Ligation; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000473:pathology; D014563:Urodynamics / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan