Phosphodiesterase 5 (PDE5) inhibition, ANP and NO rapidly reduce epididymal duct contractions, but long-term PDE5 inhibition in vivo does not

Mietens, Andrea; Tasch, Sabine; Feuerstacke, Caroline; Eichner, Gerrit; Volkmann, Jens; Schermuly, Ralph Theo; Grimminger, Friedrich; Müller, Dieter; Middendorff, Ralf

doi:10.1016/j.mce.2011.09.039

Cited by 14 publications

(15 citation statements)

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“…Notably, we observed quick phasic contractions, but no obvious tonic contractions. The frequency of spontaneous contractions monitored by time-lapse imaging was in a range between 1.5 and 15 bpm with a peak around 5–6 bpm, this resembles the contraction frequencies previously observed in organ bath studies using mid-cauda segments [15].…”

Section: Resultssupporting

confidence: 82%

“…To investigate whether spontaneous and regular contractile activity is consistently detectable in caput and corpus regions of the epididymis as previously demonstrated for mid-cauda regions by organ bath studies [15], we systematically examined various duct segments from caput and corpus regions by time-lapse imaging. A spontaneous and quite regular contraction pattern was observed in the caput and corpus segments of the epididymal duct investigated (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…Since cGMP-related signaling has been shown to reduce contractile frequency in organ bath studies using mid-cauda segments [15], we investigated whether caput and corpus regions were also susceptible to cGMP-related signaling. We investigated the effect of sGC activation through the NO donor SNP and the PDE5 inhibitor sildenafil interfering with cGMP breakdown.…”

Section: Resultsmentioning

confidence: 99%

“…ANP and CNP (both from Bachem, Weil am Rhein, Germany) were used at a final concentration of 0.1 μM, SNP (sodium nitroprusside, Fluka 71780, Buchs, Switzerland) was used at 100 μM and sildenafil (Pfizer, Karlsruhe, Germany) at 5 μM. Concentrations of the tested substances were used according to previous experiments [15], [22], [23].…”

Section: Methodsmentioning

confidence: 99%

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Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

et al. 2014

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The well orchestrated function of epididymal smooth muscle cells ensures transit of spermatozoa through the epididymal duct during which spermatozoa acquire motility and fertilizing capacity. Relaxation of smooth muscle cells is mediated by cGMP signaling and components of this pathway are found within the male reproductive tract. Whereas contractile function of caudal parts of the rat epididymal duct can be examined in organ bath studies, caput and corpus regions are fragile and make it difficult to mount them in an organ bath. We developed an ex vivo time-lapse imaging-based approach to investigate the contractile pattern in these parts of the epididymal duct. Collagen-embedding allowed immobilization without impeding contractility or diffusion of drugs towards the duct and therefore facilitated subsequent movie analyses. The contractile pattern was made visible by placing virtual sections through the acquired image stack to track wall movements over time. By this, simultaneous evaluation of contractile activity at different positions of the observed duct segment was possible. With each contraction translating into a spike, drug-induced alterations in contraction frequency could be assessed easily. Peristaltic contractions were also detectable and throughout all regions in the proximal epididymis we found regular spontaneous contractile activity that elicited movement of intraluminal contents. Stimulating cGMP production by natriuretic peptide ANP or inhibiting degradation of cGMP by the phosphodiesterase 5 inhibitor sildenafil significantly reduced contractile frequency in isolated duct segments from caput and corpus. RT-PCR analysis after laser-capture microdissection localized the corresponding molecules to the smooth muscle layer of the duct. Our time-lapse imaging approach proved to be feasible to assess contractile function in all regions of the epididymal duct under near physiological conditions and provides a tool to evaluate acute (side) effects of drugs and to investigate various signaling pathways.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

et al. 2014

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“…In all parts of the epididymis, regular contractions which elicited transport of sperm could be observed. Contraction frequency was reduced after the addition of cGMP-elevating agents sildenafil, nitric oxide (NO) or atrial natriuretic peptide (ANP) [3]. In seminiferous tubules, slow, irregular and very fine contractions of the tubular wall were observed without clear peristalsis.…”

Section: Resultsmentioning

confidence: 99%

Video microscopy as a tool to visualize cGMP effects on contractility and sperm transport in seminiferous tubules and the epididymal duct

Mietens

Eichner

Tasch

et al. 2013

BMC Pharmacol Toxicol

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Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8⁺ T cells in benign prostatic hyperplasia

et al. 2019

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Background Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5‐Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)‐dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear. Methods Paraffin‐embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH‐1 cells were cocultured with or without CD8 + T cells or PDE5‐Is in low androgen conditions for 4 days. The conditioned media, BPH‐1 cells, and CD8 + T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme‐linked immunosorbent assay. The effect of PDE5‐Is on cocultured BPH‐1/CD8 + T‐cell proliferation was detected by the cell counting kit‐8. A high‐fat diet (HFD)‐induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8 + T cells in vivo. Results CD8+ T‐cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD‐induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5‐I could suppress the CD8 + T‐cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8 + T cells by downregulating nuclear factor‐κB p65 phosphorylation, which reduced the growth of BPH‐1 through CCL5/STAT5/CCND1 signaling. Conclusions Our results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8 + T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5‐Is may be a novel, more effective treatment for BPH patients.

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Phosphodiesterase 5 (PDE5) inhibition, ANP and NO rapidly reduce epididymal duct contractions, but long-term PDE5 inhibition in vivo does not

Cited by 14 publications

References 46 publications

Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

Video microscopy as a tool to visualize cGMP effects on contractility and sperm transport in seminiferous tubules and the epididymal duct

Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8⁺ T cells in benign prostatic hyperplasia

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Phosphodiesterase 5 (PDE5) inhibition, ANP and NO rapidly reduce epididymal duct contractions, but long-term PDE5 inhibition in vivo does not

Cited by 14 publications

References 46 publications

Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

Time-Lapse Imaging as a Tool to Investigate Contractility of the Epididymal Duct – Effects of Cgmp Signaling

Video microscopy as a tool to visualize cGMP effects on contractility and sperm transport in seminiferous tubules and the epididymal duct

Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8+ T cells in benign prostatic hyperplasia

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Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8⁺ T cells in benign prostatic hyperplasia