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

• Published in: Molecular and cellular endocrinology Vol. 349; no. 2; pp. 145 - 153
• Main Authors: Mietens, Andrea, Tasch, Sabine, Feuerstacke, Caroline, Eichner, Gerrit, Volkmann, Johanna, Schermuly, Ralph Theo, Grimminger, Friedrich, Müller, Dieter, Middendorff, Ralf
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 26.02.2012
• Subjects: Adult; Aged; Aged, 80 and over; Animals; ANP; Atrial Natriuretic Factor - pharmacology; Biomedical materials; cGMP; Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Ducts; Epididymis; Epididymis - drug effects; Epididymis - physiology; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - enzymology; Hypertension, Pulmonary - physiopathology; In vivo tests; Inhibition; Male; Middle Aged; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Muscles; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitroprusside - pharmacology; Organ Culture Techniques; Partial differential equations; Phosphodiesterase 5 Inhibitors - adverse effects; Phosphodiesterase 5 Inhibitors - pharmacology; Phosphodiesterase 5 Inhibitors - therapeutic use; Piperazines - adverse effects; Piperazines - pharmacology; Piperazines - therapeutic use; Purines - adverse effects; Purines - pharmacology; Purines - therapeutic use; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Sildenafil; Sildenafil Citrate; Smooth muscle relaxation; Sulfones - adverse effects; Sulfones - pharmacology; Sulfones - therapeutic use; Surgical implants; NO; Smooth muscle relaxation; ANP; CNP; BNP; SMA; cGMP; pGC; sGC; GC-B; PDE; GC-A; Epididymis; Nitric oxide; NEP; bpm
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2011.09.039

► PDE5 localizes to smooth muscle, but not to epithelial cells, of the epididymal duct. ► Increase of cGMP by ANP, NO and PDE5 inhibition reduces epididymal duct contractility. ► PDE5 inhibition is additive to ANP and NO effects. ► PDE5 expression is unaltered in a model of long-term PDE5 inhibition in vivo. ► In this model acute cGMP effects on epididymal duct contractility are conserved. Contractility of the peritubular smooth muscle layer ensures the transit of immotile spermatozoa through the epididymal duct to acquire their fertilizing capacity. Atrial natriuretic peptide (ANP) and nitric oxide (NO) affect contractility via cGMP signals that are controlled by phosphodiesterases (PDEs). Sildenafil inhibits the cGMP-hydrolyzing PDE5 and thereby promotes relaxation of smooth muscle cells. While sildenafil is increasingly used in young patients for the treatment of pulmonary hypertension, virtually no knowledge exists about PDEs in the epididymis. Western blotting, immunohistochemistry and RT-PCR analyses after laser capture microdissection localized PDE5 to smooth muscle cells, but not to epithelial cells, of the epididymal duct in man and rat. Sildenafil, ANP and NO significantly slowed spontaneous contractions of rat epididymal duct segments in organ bath studies. Sildenafil effects were additive to ANP and NO. Long-term exposure to sildenafil in vivo did not change the PDE5 expression or the observed contractility pattern with the rapid relaxing response toward ANP, NO and sildenafil. Data demonstrate that PDE5 is an important member of cGMP signaling pathways regulating the finely orchestrated process of epididymal duct contractility and suggest, however, that in the epididymis side effects of therapeutically used sildenafil are unlikely.