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Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur

Eine immunhistochemische und funktionelle In-vitro-Studie

Significance of phosphodiesterase isoenzymes in the control of human detrusor smooth muscle function

An immunohistochemical and functional study

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Zusammenfassung

Hintergrund

Klinische Studien zeigten positive Effekte der Phosphodiesterase- (PDE-)5-Inhibitoren Sildenafil, Tadalafil und Vardenafil auf die irritative Symptomatik des benigen Prostatasyndroms. Unklar ist bisher, ob diese Substanzen auf die glatte Muskulatur in der Transitionalzone der Prostata und/oder auf den Detrusormuskel wirken. Das Ziel der Studie war die Darstellung der Expression der PDE-Isoenzyme 1, 4 und 5 in der Detrusormuskulatur und die Untersuchung der Effekte selektiver PDE-Inhibitoren auf die muskarinerge Tension isolierter glatter Muskulatur des humanen Detrusors.

Methoden

Die Darstellung der Expression von PDE-Isoenzymen erfolgte mit immunhistochemischen Methoden. Mit der Organbad-Technik wurden die Effekte der PDE-Inhibitoren Vinpocetin, Rolipram, Sildenafil, Vardenafil und Tadalafil auf die durch Carbachol induzierte tonische Kontraktion isolierter Streifenpräparate des Detrusors untersucht.

Ergebnisse

Immunreaktionen gegen die PDE-Isoenzyme stellten sich ausschließlich in der glatten Muskulatur dar. Intensiven Signalen, die spezifisch für die PDE4 und PDE5 waren, standen nur schwache Signale, welche die Expression der PDE1 zeigten, gegenüber. Die muskarinerge Kontraktion isolierter Streifenpräparate der Detrusormuskulatur wurde lediglich durch supraphysiologische Konzentrationen der PDE-Inhibitoren antagonisiert.

Schlussfolgerung

Die Studie zeigt die Expression der PDE-Isoenzyme 1, 4 und 5 im humanen Detrusor. Die relativ schwachen funktionellen Effekte der PDE-Inhibitoren lässt jedoch nicht zwangsläufig auf eine Bedeutung der PDE-Isoenzyme 1, 4 oder 5 in der Kontrolle der Relaxation der Detrusormuskulatur schließen.

Abstract

Objectives

The use of inhibitors of phosphodiesterase (PDE) isoenzymes 1 and 5 to treat overactive bladder has been suggested. To further evaluate the significance of PDE isoenzymes in detrusor smooth muscle relaxation, we investigated the effects of selective PDE inhibitors on the tension induced by carbachol of isolated human detrusor tissue. Using immunohistochemical methods, the expression of PDE1, PDE4, and PDE5 in human detrusor was also investigated.

Material and Methods

The expression of PDE1, PDE4, and PDE5 was evaluated by means of conventional immunohistochemistry (IHC). Using the organ bath technique, the effects of the PDE inhibitors vinpocetine, rolipram, sildenafil, tadalafil, and vardenafil on the tension induced by the muscarinic agonist carbachol (1 µM) were investigated.

Results

The tension induced by carbachol was dose-dependently reversed by the PDE inhibitors; the maximum reversal of tension ranged from 7% (tadalafil) to 34% (vardenafil). IHC revealed that the expression of PDE isoenzymes was limited to the smooth musculature of the detrusor. While there was prominent expression of PDE4 and PDE5, immunoreactions indicating the presence of PDE1 were less abundant.

Conclusion

Despite the fact that inhibitors of PDE1, PDE4, and PDE5 exerted only a weak relaxant response on detrusor strips precontracted by carbachol, our findings indicate that both the cAMP and cGMP pathways might be involved in the relaxation mechanism of human detrusor smooth muscle.

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Diese Studie wurde mit einem Forschungsstipendium der Bayer Healthcare AG, Geschäftsbereich Bayer Vital GmbH (Leverkusen, Wuppertal), unterstützt. Die Autoren Drs. Peter Sandner und Ernst Ulbrich sind Mitarbeiter der Fa. Bayer Healthcare AG (Bayer Vital GmbH), Leverkusen/Wuppertal. Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

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Authors and Affiliations

  1. Klinik für Urologie und Uro-Onkologie, Zentrum Chirurgie, Medizinische Hochschule Hochschule (MHH), Carl-Neuberg-Straße 1, 30625, Hannover, Deutschland

    S. Ückert, E.S. Waldkirch, M. Oelke & M.A. Kuczyk

  2. Urologische Klinik und Poliklinik, Medizinische Fakultät, Klinikum Großhadern, Ludwig-Maximilians-Universität, München, Deutschland

    K. Sigl & C.G. Stief

  3. Geschäftsbereich Urologie/Andrologie, Bayer HealthCare AG, Bayer Vital GmbH, Leverkusen, Deutschland

    P. Sandner & E. Ulbrich

Authors
  1. S. Ückert
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  2. K. Sigl
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  3. E.S. Waldkirch
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  4. P. Sandner
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  5. E. Ulbrich
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  6. M. Oelke
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  7. C.G. Stief
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  8. M.A. Kuczyk
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Corresponding author

Correspondence to S. Ückert.

Additional information

Die in diesem Manuskript zusammengefassten Ergebnisse wurden im wissenschaftlichen Programm des 19. Arbeitstreffens des Forum Urodynamicum e.V., Amsterdam, Niederlande, 07.03. und 08.03.2008, präsentiert.

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Ückert, S., Sigl, K., Waldkirch, E. et al. Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur. Urologe 48, 764–769 (2009). https://doi.org/10.1007/s00120-009-1970-z

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  • DOI: https://doi.org/10.1007/s00120-009-1970-z

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