Abbreviations & Acronyms ACE = angiotensin-converting enzyme AngII = angiotensin II AT1 = angiotensin II type 1 receptor ATP = adenosine 5′-triphosphate BPH = benign prostatic hyperplasia BOO = bladder outlet obstruction Cch = carbachol cDNA = complementary deoxyribonucleic acid C/M = collagen fiber-to-smooth muscle Ct = comparative threshold cycle DNA = deoxyribonucleic acid EFS = electrical field stimulation HB-EGF = heparin-binding epidermal growth factor-like growth factor KCl = potassium chloride mRNA = messenger ribonucleic acid rRNA = ribosomal ribonucleic acid NOX1 = nicotinamide adenine dinucleotide phosphate oxidase 1 PCR = polymerase chain reaction RAS = renin-angiotensin system SMC = smooth muscle cells TGF-b1 = transforming growth factor-b1 Objectives: To determine whether long-term administration of an angiotensin II type 1 receptor antagonist improves morphology and function in obstructed bladders. Methods: Male Sprague-Dawley rats underwent surgery to produce bladder outlet obstruction (bladder outlet obstruction group; n = 32) or sham surgery (sham group; n = 16). A total of 2 weeks later, 16 bladder outlet obstruction-rats were given the AT1 antagonist, candesartan, subcutaneously (candesartan group) using an osmotic pump for 4 weeks; the remaining bladder outlet obstruction-rats received vehicle (bladder outlet obstruction group). A total of 6 weeks after surgery, we compared continuous cystometry, bladder weight, strip contraction, histology and messenger ribonucleic acid expression of growth factors, nicotinamide adenine dinucleotide phosphate oxidase 1 and renin-angiotensin system components among the three groups. Results: Bladder weights markedly increased with bladder outlet obstruction (578 Ϯ 159 mg), and candesartan (344 Ϯ 111 mg) suppressed this increase. Micturition pressure, which was significantly higher with bladder outlet obstruction, was unaffected by candesartan. The shortened micturition interval and decreased micturition volume with bladder outlet obstruction were significantly prolonged and increased by candesartan. Candesartan also significantly decreased residual urine. Histologically, the collagen fiber-to-muscle ratio was significantly increased with bladder outlet obstruction (0.85 Ϯ 0.25) compared with the sham group (0.53 Ϯ 0.18); this increase was suppressed by candesartan (0.49 Ϯ 0.21). The messenger ribonucleic acid expression of heparin-binding epidermal growth factor-like growth factor, transforming growth factor-b1 and nicotinamide adenine dinucleotide phosphate oxidase 1 significantly increased with bladder outlet obstruction, but it was significantly reduced by candesartan. Compared with the bladder outlet obstruction group, candesartan increased the maximal contraction of bladder strips for all stimuli except for angiotensin II. Conclusion: These findings suggest that bladder angiotensin II type 1 receptors contribute to the pathophysiology of remodeling and dysfunction in obstructed bladder.
Bladder hypertrophy and dysfunction are well-known bladder responses to outlet obstruction (i.e. urodynamic overload). Cardiac hypertrophy and heart failure are also caused by hemodynamic overload, and many basic and clinical studies suggest that the local renin-angiotensin system (RAS) has a crucial role in load-induced cardiac pathogenesis. The similarity of the response of the heart and the bladder to overload suggests that angiotensin II (AngII) may have a similar regulatory role in pathological remodeling, such as muscle growth and collagen production of the obstructed bladder. Previous in vitro studies show that angiotensin I is converted to AngII by angiotensin converting enzyme (ACE) or chymase, which exists in the human bladder. In addition, many studies using contractile responses to AngII, autoradiography, radioreceptor assay and mRNA expression demonstrate the presence of AngII receptor in the bladder from various animals and the human. Recent evidence indicates that AngII is released from bladder smooth muscle cells (SMCs) in response to a repetitive stretch stimulus, and subsequently activates AT1 in an autocrine fashion. This AT1 activation has been shown to mediate heparin-binding epidermal growth factor-like growth factor gene expression and to increase the DNA synthesis rate of bladder SMCs. Consistent with this in vitro study, previous studies and our preliminary data suggest the usefulness of AT1 antagonists or ACE inhibitor in bladder outlet obstruction of the rabbit and rat. Taken together, the local RAS contributes to structural and functional alterations in the bladder after obstruction.Key words angiotensin converting enzyme inhibitor, angiotensin II type 1 receptor antagonist, bladder hypertrophy, bladder outlet obstruction, renin angiotensin system
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