Effects of Mirodenafil, a Phosphodiesterase-5 Inhibitor, on Female Rat Bladder in a Partial Bladder Outlet Obstruction Model: Physiological and Immunohistochemical Aspects

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Abstract

Purpose

We investigated the effects of mirodenafil, a phosphodiesterase-5 inhibitor developed in South Korea, on the female rat bladder in a partial bladder outlet obstruction (BOO) model.

Materials and Methods

Thirty-six female Sprague-Dawley rats were divided into four groups: the control group, BOO without medication group, BOO with mirodenafil 1 mg/kg group, and BOO with mirodenafil 4 mg/kg group. Mirodenafil was administered orally for 2 weeks after the induction of BOO. Two weeks after BOO, the rats in each group underwent cystometry under urethane anesthesia. After cystometry, the bladder was excised to perform immunohistochemical staining for connexin 43.

Results

The three BOO groups showed significant increases in mean bladder weight compared with the control group. Baseline pressure, threshold pressure, and maximum contraction pressure were not significantly different between the four groups. Although the contraction interval was decreased in all BOO groups compared with the control group, it was prolonged in the two groups treated with mirodenafil compared with the untreated BOO group. In the immunohistochemical examination, connexin 43 staining intensity in the lamina propria increased in the three BOO groups compared with the control group. The two groups treated with mirodenafil, however, showed decreased connexin 43 staining compared with the untreated BOO group.

Conclusions

Mirodenafil may increase the contraction intervals of female rat bladders in a partial BOO model. Decreasing bladder overactivity by mirodenafil may be related to intracellular communication mechanisms involving connexin 43.

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Most cited references 15

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Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Kevin T. McVary, Claus Roehrborn, Jed C Kaminetsky … (2007)

We assessed the efficacy and safety of tadalafil dosed once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia. Following a 4-week, single-blind, placebo run-in 281 men were randomly assigned (1:1) to 5 mg tadalafil for 6 weeks, followed by dose escalation to 20 mg for 6 weeks or 12 weeks of placebo. Tadalafil significantly improved the mean change from baseline in International Prostate Symptom Score at 6 weeks (5 mg tadalafil -2.8 vs placebo -1.2) and at 12 weeks (5/20 mg tadalafil -3.8 vs placebo -1.7). Larger changes were observed with inclusion of the placebo run-in at 12 weeks (5/20 mg tadalafil -7.1 vs placebo -4.5). Significant improvements were also seen in the International Prostate Symptom Score irritative and obstructive domains, the International Prostate Symptom Score quality of life index, a question about urinary symptom improvement and the Benign Prostatic Hyperplasia Impact Index (significant at 12 weeks) vs placebo. International Prostate Symptom Score and International Index of Erectile Function erectile function domain scores significantly improved in the 56% of men with lower urinary tract symptoms/benign prostatic hyperplasia who were sexually active and had erectile dysfunction. Changes in uroflowmetry parameters were similar in the placebo and tadalafil groups. Commonly reported (2% or greater) treatment emergent adverse events were "erection increased," dyspepsia, back pain, headache, nasopharyngitis and upper respiratory tract infection (each 5.1% or less). No change in post-void residual volume was seen with tadalafil treatment. Tadalafil once daily was well tolerated and demonstrated clinically meaningful and statistically significant symptomatic improvement for lower urinary tract symptoms/benign prostatic hyperplasia. Tadalafil also improved erectile function in men with lower urinary tract symptoms and erectile dysfunction.

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Gap junctions and connexin expression in human suburothelial interstitial cells.

Nicholas J. Severs, G Sui, Brendan C. Fry … (2002)

To determine whether suburothelial interstitial cells of the human bladder express gap junctions, and if so, to establish their extent and composition, using immunocytochemistry, confocal microscopy and electron microscopy. Bladder tissue was obtained at cystectomy; the tissue was: (i) frozen for cryosectioning and Northern blot analysis; (ii) fixed and embedded for standard thin-section electron microscopy; and (iii) processed using low-denaturation conditions in Lowicryl for immunogold-label electron microscopy. Cryosections were immunofluorescently labelled using antibodies against connexins 43, 40 and 45, vimentin, desmin and c-Kit ligand, and examined by confocal microscopy. Double labelling was used to determine the spatial relationship of labelling for connexin43 with that of vimentin and desmin. Thin-section electron microscopy was used to investigate interstitial cell ultrastructure and permit unequivocal identification of gap junctions, and immunogold labelling of Lowicryl sections was applied to localize connexin43. Immunoconfocal microscopy showed prominent labelling for the gap junction protein, connexin43, in a suburothelial band of cells that was also strongly positive for vimentin. The connexin43/vimentin-positive cells showed only weak labelling for desmin and c-Kit ligand, and were immunonegative for connexins 40 and 45. Northern blotting showed a corresponding abundance of connexin43 transcript in the mucosal layer but not the detrusor layer of the bladder wall. Electron microscopy revealed abundant gap junctions, recognized by their pentalaminar structure, between the cell processes of interstitial cells in the suburothelial zone. That these interstitial cell gap junctions were the source of the connexin43 immunolabelling observed by immunoconfocal microscopy was confirmed by immunogold labelling in sections of Lowicryl-embedded tissue examined by electron microscopy. A network of interstitial cells, extensively linked by connexin43-containing gap junctions, is located beneath the urothelium in human bladder. As gap junctions provide pathways for direct cell-to-cell communication, the interstitial cellular network may operate as a functional syncytium, integrating signals and responses in the bladder wall.

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Role of gap junctions in spontaneous activity of the rat bladder.

Yasutaka Ikeda, Brendan C. Fry, Timothy D. Griffiths … (2007)

Increased gap junction expression in lamina propria myofibroblasts and urothelial cells may be involved in detrusor overactivity, leading to incontinence. Immunohistochemistry was used to compare connexin (Cx) 26, 43, and 45 expression in the bladders of neonatal, adult, and spinal cord-transected rats, while optical imaging was used to map the spread of spontaneous activity and the effects of gap junction blockade. Female adult Sprague-Dawley rats were deeply anesthetized, a laminectomy was performed, and the spinal cord was transected (T8/T9). After 14 days, their bladders and those of age-matched adults (4 mo old) and neonates (7-21 day old) were excised and studied immunohistochemically using frozen sections or optically using whole bladders stained with voltage- and Ca(2+)-sensitive dyes. The expression of Cx26 was localized to the urothelium, Cx43 to the lamina propria myofibroblasts, and Cx45 to the detrusor smooth muscle. While the expression of Cx45 was comparable in all bladders, the expression of Cx43 and Cx26 was increased in neonate and transected animals. In the bladders of adults, spontaneous activity was initiated at multiple sites, resulting in a lack of coordination. Alternatively, in neonate and transected animals spontaneous activity was initiated at a focal site near the dome and spread in a coordinated fashion throughout the bladder. Gap junction blockade (18beta-glycyrrhetinic acid, 1 microM) abolished this coordinated activity but had no effect on the uncoordinated activity in adult bladders. These data suggest that coordinated spontaneous activity requires gap junction upregulation in urothelial cells and lamina propria myofibroblasts.

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Author and article information

Journal

Journal ID (nlm-ta): Korean J Urol

Journal ID (iso-abbrev): Korean J Urol

Journal ID (publisher-id): KJU

Title: Korean Journal of Urology

Publisher: The Korean Urological Association

ISSN (Print): 2005-6737

ISSN (Electronic): 2005-6745

Publication date (Print): May 2013

Publication date (Electronic): 14 May 2013

Volume: 54

Issue: 5

Pages: 339-344

Affiliations

Department of Urology, Eulji General Hospital, Seoul, Korea.

[1 ]Department of Pathology, Eulji General Hospital, Seoul, Korea.

[2 ]Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Author notes

Corresponding Author: Kwang Myung Kim. Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. TEL: +82-2-760-2407, FAX: +82-2-747-9824, kwang@ 123456plaza.snu.ac.kr

Article

DOI: 10.4111/kju.2013.54.5.339

PMC ID: 3659229

PubMed ID: 23700501

SO-VID: 116fbe0c-576e-4160-b60f-e744bbca5279

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Effects of Mirodenafil, a Phosphodiesterase-5 Inhibitor, on Female Rat Bladder in a Partial Bladder Outlet Obstruction Model: Physiological and Immunohistochemical Aspects

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Abstract

Purpose

Materials and Methods

Results

Conclusions

Related collections

Animal models of intrauterine growth restriction (IUGR)

Most cited references 15

Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia.

Gap junctions and connexin expression in human suburothelial interstitial cells.

Role of gap junctions in spontaneous activity of the rat bladder.

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