Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

Müller, Dieter; Mukhopadhyay, Amal K.; Davidoff, M; Middendorff, Ralf

doi:10.1530/rep-10-0517

Cited by 19 publications

(22 citation statements)

References 50 publications

(71 reference statements)

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“…However, this study did not examine bladder. More recently, an apparently even higher expression of PDE5 in bladder compared with prostate, testis, and epididymis was reported (48). Examination of human tissues revealed similar findings (16,47).…”

mentioning

confidence: 59%

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Zhang

Zang

Wei

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROK␤ mRNA, whereas it increased eNOS plus ␣ 1a and ␣1b adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH. benign prostatic hyperplasia; contraction; lower urinary tract symptoms; phosphodiesterase 5; phosphodiesterase 5 inhibitors; smooth muscle myosin; nitric oxide BENIGN PROSTATIC HYPERPLASIA (BPH), a cause of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in aging men, is a common pathological process with a histological prevalence of ϳ50 -60% for men in their 60s and 80 -90% for men in their 70s and 80s (54). Although the etiology of prostatic hyperplasia is not well understood, androgens and aging are necessary for the development of BPH (55) containing two physiological components, static (increased prostate size) (40) and dynamic [increased prostatic smooth muscle (SM) tone] (11).The dynamic tone of prostatic SM is regulated mainly by the ␣ 1 -adrenoreceptor (72), with up to 50% of the total urethral pressure in BPH patients being attributed to ␣-adrenoreceptormediated muscle tone (18), and ␣ 1 -blockers are the first-line therapy for BPH. Three major subtypes of adrenoreceptors have been identified to exist in the prostate at the molecular level (␣ 1a , ␣ 1b , and ␣ 1d ) (15). Eckert et al. (14), using a patch clamp combined with the fura-2 fluorescence calcium labelin...

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confidence: 59%

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Zhang

Zang

Wei

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…In SM tissues the isoforms cGKIa and cGKIb mediate relaxation by both calcium-dependent and calcium-independent pathways (Waldmann et al, 1986;Wernet et al, 1989;Keilbach et al, 1992;Surks, 2007). Recent articles support an essential role for cGKI in SMC relaxation in the male reproductive tract (Mewe et al, 2006;Muller et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Partial loss of contractile marker proteins in human testicular peritubular cells in infertility patients

et al. 2012

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SUMMARYFibrotic remodelling of the testicular tubular wall is common in human male infertility caused by impaired spermatogenesis. We hypothesized that this morphological change bears witness of an underlying fundamentally altered state of the cells building this wall, that is, peritubular smooth muscle-like cells. This could include a loss of the contractile abilities of these cells and thus be a factor in male infertility. Immune cells are increased in the tubular wall in these cases, hence local immune cell-related factors, including a prostaglandin (PG) metabolite may be involved. To explore these points in the human, we used testicular biopsies, in which tubules with normal spermatogenesis and impaired spermatogenesis are next to each other [mixed atrophy (MA)], normal biopsies and cultured human testicular peritubular cells. Proteins essential for contraction, myosin heavy chain (MYH11), calponin (Cal) and relaxation, cGMP-dependent protein kinase 1 (cGKI), were readily detected by immunohistochemistry and were equally distributed in all peritubular cells of biopsies with normal spermatogenesis. In all biopsies, vascular smooth muscle cells also stained and served as important intrinsic controls, which showed that in MA samples when spermatogenesis was impaired, staining was restricted to only few peritubular cells or was absent. When spermatogenesis was normal, regular peritubular staining became obvious. This pattern suggests complex regulatory influences, which in face of the identical systemic hormonal situation in MA patients, are likely caused by the local testicular micromilieu. The PG metabolite 15dPGJ2 may represent such a factor and it reduced Cal protein levels in peritubular cells from patients with/without impaired spermatogenesis. The documented phenotypic switch of peritubular, smooth muscle-like cells in MA patients may impair the abilities of the afflicted seminiferous tubules to contract and relax and must now be considered as a part of the complex events in male infertility.

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“…Some previous studies have demonstrated high levels of PDE-5 enzyme activity in the bladder [28,29]. Because TDL selectively inhibits the PDE-5 enzyme which is responsible for the breakdown of cGMP, the drug led to increased levels of cGMP in the bladder tissue.…”

Section: Discussionmentioning

confidence: 98%

Effects of Tadalafil on Hemorrhagic Cystitis and Testicular Dysfunction Induced by Cyclophosphamide in Rats

Yiğitaslan¹,

Özatik²,

Özatik

et al. 2013

Urol Int

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Introduction: The protective and/or therapeutic potential of tadalafil (TDL) on cyclophosphamide (CP)-induced hemorrhagic cystitis (HC) and testicular dysfunction in rats was evaluated. Materials and Methods: The animals except from the control group were divided into four groups and treated with saline, or 1, 5 or 10 mg/kg TDL orally (CP, TDL1, TDL5 and TDL10 groups, respectively) before and after CP injection. Body and organ weights, sperm count, cGMP, nitric oxide (NO), IL-6 and IL-10 levels in serum and bladder tissue, and serum testosterone (T), LH and FSH levels were determined. The histological analysis of bladder and testis was performed and the number of apoptotic cells was determined. Results and Conclusion: The CP group had decreased cGMP and NO levels in the bladder, serum T level (p < 0.05) and sperm count (p < 0.001) and higher IL-6 levels in serum and bladder (p < 0.01). Treatment with TDL resulted in increased cGMP (p < 0.001), NO (p < 0.05) and serum T (p < 0.05) levels. Histological analysis of the CP group showed severe HC in bladder and testicular damage. TDL-treated animals showed a dose-dependent improvement in all of these histological impairments. In conclusion, a selective inhibitor of phosphodiesterase-5 enzyme, TDL, showed a protective and/or therapeutic effect on CP-induced HC and testicular dysfunction in rats.

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Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

Cited by 19 publications

References 50 publications

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

Partial loss of contractile marker proteins in human testicular peritubular cells in infertility patients

Effects of Tadalafil on Hemorrhagic Cystitis and Testicular Dysfunction Induced by Cyclophosphamide in Rats

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