Angiotensin II type 1 (AT‐1) receptor inhibition partially prevents the urodynamic and detrusor changes associated with bladder outlet obstruction: a mouse model

Abstract

8 4 1What ' 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). MATERIALS AND 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 fi rst 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 μ m thick), 2 = normal (100 -200 μ m thick), 3 = hypertrophy ( > 200 μ m thick) compared with controls. RESULTS• Compared with controls, BOO mice had greater C (153.5 ± 20.9 vs 57.5 ± 7.4 μ l, 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 μ L, P = 0.01), no signifi cant 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 insignifi cant reduction in mean bladder weight (68.1 ± 9.1 mg vs 93.2 ± 11.7 mg, P = 0.10), but a signifi cant reduction in detrusor muscle thickness (median 2 vs 3, P = 0.02). Losartan did not mediate any signifi cant structural or functional changes in the unobstructed mouse bladder. CONCLUSION• In a mouse model of BOO, treatment with an AT-1 antagonist partially prevented the urodynamic and structural changes that otherwise occur with BOO. KEYWORDSangiotensin II , bladder outlet obstruction , benign prostatic enlargement , detrusor overactivity , detrusor hypertrophy Study Type -Therapy (case control) Level of Evidence 3b

Pharmacological Modulation of Mucosa-Related Impairment of β-Adrenoceptor-Mediated Relaxation in Human Detrusor

“…The lower urinary tract harbors a local renin-angiotensin system [30] that contributes to stress incontinence in animal models [31]. A post hoc analysis of antihypertensive patients treated with AT 1 receptor blockers revealed lesser lower urinary tract symptoms than the untreated subjects [32].…”

What was hot at the joint ICS and IUGA meeting Toronto, Canada, 23–27 August 2010

“…The angiotensin II receptor inhibitor has been shown to reduce detrusor hypertrophy and fibrosis associated with bladder outflow obstruction in the rat model (Abstract 15). 59 In addition to this detrusor overactivity was reduced. These results suggest angiotensin II may provide a means by which the detrusor responds to increased work load or ischemia.…”

Local renin–angiotensin systems in the genitourinary tract

“…This contractile effect of Ang II appears to be mediated by the AT1 receptor (Tanabe et al 1993;Yamada et al 2009). Comiter and Phull (2011) demonstrated that AT-1 receptor antagonism indeed inhibits the increase in nonvoiding contractions that normally occur following bladder outflow obstruction in a mouse model-analogous to detrusor overactivity in men with benign prostatic obstruction. It has been hypothesized that inhibition of frequent high-pressure isovolumetric contraction, by preventing repeated mechanical stress, prevents the detrusor hypertrophy.…”

“…In a canine model, Shirazi et al (2008) showed that Ang II inhibition did, in fact, prevent collagen deposition in the bladder, but did not significantly affect detrusor muscular content in the setting of BOO. Most recently, Comiter and Phull (2011) demonstrated that chronic AT1 receptor antagonism with losartan, at the time of BOO, did in fact partly prevent the hypertrophic changes that otherwise occurred in a rat model of urethral obstruction.…”

“…It has been hypothesized that inhibition of frequent high-pressure isovolumetric contraction, by preventing repeated mechanical stress, prevents the detrusor hypertrophy. As the workload of the bladder is reduced, the smooth muscle hypertrophic response to obstruction is reduced (Comiter and Phull 2011).…”