Zusammenfassung
Hintergrund
PDE-5-Inhibitoren stellen den Goldstandard in der medikamentösen Therapie der erektilen Dysfunktion (ED) dar. Viel versprechende Ergebnisse werden auch für weitere urologische Indikationen wie der Harnleiterkolik berichtet. Ziel der vorliegenden Arbeit war es daher, die funktionellen Effekte der PDE-5-Inhibitoren Sildenafil (SIL), Vardenafil (VAR) und Tadalafil (TAD) sowohl auf die Muskelspannung als auch auf die Konzentration zyklischer Nukleotide in der glatten Muskulatur des menschlichen Harnleiters in vitro zu testen.
Material und Methoden
Die relaxierenden Eigenschaften der PDE-5-Inhibitoren wurden mit der Organbadtechnik untersucht; der cAMP- sowie cGMP-Gehalt wurde mit spezifischen Radioimmunoassays bestimmt.
Ergebnisse
Die verschiedenen PDE-5-Inhibitoren relaxierten die Muskelspannung in der Rangfolge Var>Sil>Tad. Der cGMP-Spiegel wurde lediglich von Var auf das 3,3Fache erhöht; ein signifikanter Anstieg der cAMP-Spiegel war nicht zu verzeichnen.
Schlussfolgerung
Unsere Daten unterstreichen die Bedeutung von cGMP in der Regulation der glatten Muskulatur menschlichen Harnleiters. PDE-5-Inhibitoren könnten somit bei der Behandlung einer Harnleiterkolik zum Einsatz kommen.
Abstract
Background
PDE5 inhibitors represent the gold standard in the medical therapy of erectile dysfunction (ED). Promising results have been published regarding further urological indications such as treatment of ureteral colic. The aim of the present study was to evaluate the functional effects of the PDE5 inhibitors sildenafil (SIL), vardenafil (VAR), and tadalafil (TAD) on tissue tension and cyclic nucleotide levels of human ureteral smooth muscle segments in vitro.
Methods
Relaxant responses of human ureteral smooth muscle were investigated in vitro using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by specific radioimmunoassays.
Results
Relaxing effects of ureteral muscle tension were observed in the rank order VAR > SIL > TAD. While only VAR significantly elevated cGMP levels 3.3-fold over control, no increase for cAMP levels was observed.
Conclusions
Our data provide evidence that cGMP is involved in the control of the normal function of the smooth musculature of the human ureter. Our findings suggest the potential of using selective inhibitors of PDE isoenzymes in the treatment of ureteral colic.
Literatur
Moe OW (2006) Kidney stones: pathophysiology and medical management. Lancet 367: 333–344
Coll DM, Varanelli MJ, Smith RC (2002) Relationship of spontaneous passage of ureteral calculi to stone size and location as revealed by unenhanced helical CT. AJR Am J Roentgenol 178: 101–103
Roberts WW, Cadeddu JA, Micali S et al. (1998) Ureteral stricture formation after removal of impacted calculi. J Urol 159: 723–726
Porpiglia F, Destefanis P, Fiori C, Fontana D (2000) Effectiveness of nifedipine and deflazacort in the management of distal ureter stones. Urology 56: 579–582
Sivrikaya A, Celik OF, Sivrikaya N, Ozgur GK (2003) The effect of diclofenac sodium and papaverine on isolated human ureteric smooth muscle. Int Urol Nephrol 35: 479–483
Ahmad M, Chaughtai MN, Khan FA (1991) Role of prostaglandin synthesis inhibitors in the passage of ureteric calculus. J Pak Med Assoc 41: 268–270
Cervenakov I, Fillo J, Mardiak J et al. (2002) Speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1-blocker Tamsulosin. Int Urol Nephrol 34: 25–29
Dellabella M, Milanese G, Muzzonigro G (2003) Efficacy of tamsulosin in the medical management of juxtavesical ureteral stones. J Urol 170: 2202–2205
Pozzan T, Rizzuto R, Volpe P, Meldolesi J (1994) Molecular and cellular physiology of intracellular calcium stores. Physiol Rev 74: 595–636
Schmidt HH, Lohmann SM, Walter U (1993) The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta 1178: 153–175
Briganti A, Salonia A, Deho‘ F et al. (2005) Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction. World J Urol 23: 374–384
Sairam K, Kulinskaya E, McNicholas TA et al. (2002) Sildenafil influences lower urinary tract symptoms. BJU Int 90: 836–839
McVary T, Roehrborn CG, Kaminetsky JC et al. (2006) The efficacy and safety of tadalafil administered once a day for lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia. Eur Urol 5(Suppl 2): 196
Truss MC, Stief CG, Uckert S et al. (2001) Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol 19: 344–350
Berman JR, Berman LA, Lin H et al. (2001) Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 27: 411–420
Taher A, Schulz-Knappe P, Meyer M et al. (1994) Characterization of cyclic nucleotide phosphodiesterase isoenzymes in the human ureter and their functional role in vitro. World J Urol 12: 286–291
Kühn R, Uckert S, Stief CG et al. (2000) Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways. Urol Res 28: 110–115
Saighi D, Zerbib M, Thiounn N et al. (2000) In vitro study of the modulation of human ureteral tonus by nitric oxide and zaprinast, a phosphodiesterase inhibitor. Prog Urol 10: 1161–1168
Becker AJ, Stief CG, Meyer M et al. (1998) The effect of the specific phosphodiesterase-IV-inhibitor rolipram on the ureteral peristalsis of the rabbit in vitro and in vivo. J Urol 160: 920–925
Nicholson CD, Challiss RA, Shahid M (1991) Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci 12: 19–27
Jeremy JY, Ballard SA, Naylor AM et al. (1997) Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br J Urol 79: 958–963
Chuang AT, Strauss JD, Murphy RA, Steers WD (1998) Sildenafil, a type-5 CGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol 160: 257–261
Stief CG, Uckert S, Truss MC et al. (1996) A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro. Urol Res 24: 333–337
Lau LC, Adaikan PG (2006) Mechanisms of direct relaxant effect of sildenafil, tadalafil and vardenafil on corpus cavernosum. Eur J Pharmacol 541: 184–190
Nies AT, Spring H, Thon WF et al. (2002) Immunolocalization of multidrug resistance protein 5 in the human genitourinary system. J Urol 167: 2271–2275
Holdgate A, Carissa MO (2005) Is there a role for antimuscarinics in renal colic? A randomized controlled trial. J Urol 174: 572–575
Interessenkonflikt
Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gratzke, C., Ückert, S., Reich, O. et al. PDE-5-Inhibitoren. Urologe 46, 1219–1223 (2007). https://doi.org/10.1007/s00120-007-1409-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00120-007-1409-3