Use of Bosentan, Theophylline and Vardenafil in Treatment of Priapism

Öz

Objective: To evaluate the early therapeutic alternatives such as Bosentan an Endothelin receptor blocker, Theophylline and Adenosin receptor blocker and Vardenafil a non-selective Phosphodiesterase 5 enzyme inhibitor for the therapy of ischemic priapism in the rat models.
Methods: Twenty-four Sprague-Dawley rats were randomly divided into 4 equal groups. Control group, Vardenafil group, Bosentan group and Theophylline group. Erection was provided by vacuum constriction method and it was maintained for 4 hours for achieving the priapism in all groups. Then, Six rats from each group were sacrificed by cervical dislocation. Consequently, cavernous tissue samples were collected and placed in the tissue bath. Tissue samples were prepared as 0.5-0.2 cm. strips and put into heat jacketed double walled organ bath containing 37°C krebs solution which is constantly bubbled with 95% O2 and 5 % CO2 and mounted at a resting tension of 1000 mg. After taking the 1 hour record of the three groups except the control group, Bosentan, Theophylline and Vardenafil were admitted in increasing doses. Consequently the alterations of the contractions in the strips due to the drugs and their increasing doses are observed.
Results: In this study we detected that Bosentan increased the frequency and amplitude of the contractions of the cavernous tissue in the Priapism status in a statistically significant manner, Theophylline decreased the frequency and the amplitude significantly and Vardenafil had statistically no effect on the frequency and amplitude.
Conclusion: Inhibition of priapism induced apoptosis with Bosentan, seems promising on preserving erectile function.
Key words: Bosentan, ischemic priapism, theophylline, vardenafil

Anahtar Kelimeler

• -

Priapizm Tedavisinde Bosentan, Teofilin ve Vardenafil Kullanımı

Öz

Amaç: Endotelin reseptör blokeri olan Bosentan, Adenozin reseptör blokeri olan Teofilin ve non selektif Fosfodiesteraz 5 enzimi inhibitörü olan Vardenafil’in iskemik Priapizm oluşturulmuş rat modelinde terapötik etkinliğinin araştırılması hedeflendi. Yöntemler: Randomize olarak 24 Sprague-Dawley rat kontrol grubu, Vardenafil grubu, Bosentan grubu ve Teofilin grubu olmak üzere 4 eşit gruba dağıtıldı. Ereksiyon her grupta vakum konstriksiyon metodu ile sağlandı ve priapizm sağlanması için 4 saat sürdürüldü. Daha sonra her gruptaki 6 rata Servikal dislokasyon yöntemi ile dekapitasyon uygulandı. Kavernöz dokular ayrıldı ve organ banyosuna bırakıldı. Doku örnekleri 0,5-0,2 cm. şeritler şeklinde ısı çeperli, çift duvarlı içinde 37°C krebs çözeltisi bulunan ve devamlı 95% O2 ve 5% CO2 ile gazlandırılan organ banyolarına istirahat gerimi 1000 mg. olacak şekilde asıldılar. Kontrol grubu dışında kalan grupların 1 saatlik kasılma kayıtları alındıktan sonra grubuna göre artan dozlarda Bosentan, Teofilin ve Vardenafil uygulandı ve şeritlerdeki ilaç ve doz bağımlı kontraksiyon değişiklikleri gözlendi.Bulgular: Bu çalışmada Bosentanın priapizm oluşturulmuş Kavernöz doku kasılmalarında frekans ve amplitüdleri istatiksel olarak anlamlı şekilde arttırıp Teofilinin ise yine anlamlı bir şekilde azalttığı gözlendi. Vardenafilin ise frekans ve amplitüd üzerinde herhangi bir etkisi gözlenmedi. Sonuç: Priapizm ile indüklenmiş apoptozisin Bosentan ile inhibe edilmesi erektil fonksiyonun korunması açısından umut vaat etmektedir

Anahtar Kelimeler

• Bosentan, iskemik priapizm, teofilin, vardenafil

Kaynakça

1. Montague DK, Jarow J, Broderick GA, et al. American urological
2. association guideline on the management of priapism. J Urol 2003;170:1318-1324.
3. Hinman F Priapism: Report of cases in a clinical study of the literature with reference to its pathogenesis and surgical treatments. Ann Surg 1914;60:689-716.
4. Burnett AL. Neorophysiology of erectile function: Androgenic effects. J Androl. 2003;24:S2-5.
5. Yuan J, DeSouza R, Westney OL, et al. Insights of priapism
6. mechanism and rationale treatment for recurrent priapism. Asian J Androl 2008;10:88-101.
7. Pautler SE, Brock GB. Priapism. Urol Clin North Am 2001;28:391-403.
8. Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction and priapism. In: Walsh PC, Retik AB,Vaughan ED Jr,Wein AJ,Kavoussi AR,et al, editors. Campbell’s Urology. Philadelphia: WB Saunders,2002.1610-16967.

9. Fredholm BB, AP IJ, Jacobson KA, et al. International union of pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001;53:527-552.
10. Lad PM, Nielsen TB, Londos C, et al. Independent mechanisms of adenosine activation and inhibition of the turkey erythrocyte adenylate cyclase system. J Biol Chem 1980;255:10841-10846.
11. Cooper DM, Londos C, Rodbell M. Adenosine receptor-mediated
12. inhibition of rat cerebral cortical adenylate cyclase by a GTP-dependent process. Mol Pharmacol 1980;18:598-601.
13. Londos C, Cooper DM, Wolff J. Subclasses of external adenosine
14. receptors. Proc Natl Acad Sci U S A 1980;77:2551-2554.
15. Palmer TM, Stiles GL. Identification of an A2a adenosine receptor domain specifically responsible for mediating short-term desensitization. Biochemistry 1997;36:832-838.
16. Stiles GL. Adenosine receptor subtypes: new insights from cloning and functional studies. In: Jacobson KA, Jarvis MF, editors. Purinergic approaches in experimental therapeutics. New York: Wiley-Liss Inc 1997: 29-37.
17. Lin CS, Lin G, Lue TF. Cyclic nucleotide signaling in cavernous smooth muscle. J Sex Med 2005;2:478- 491.
18. Yingbo Dai, Yujin Zhang, Phatarpekar MS, et al. Adenosine Signaling, Priapism and Novel Therapies. J Sex Med 2009;6:292-301.
19. Chiang PH, Wu SN, Tsai EM, et al. Adenosine modulation of neurotransmission in penile erection. Br J Clin Pharmacol 1994;38:357-362.
20. Mi T, Abbasi S, Zhang H, et al. Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest 2008;118:1491-501.
21. Granchi S, Vannelli GB, Vignozzi L, et al. Expression and regulation of endothelin-1 and its receptors in human penile smooth muscle cells. Mol Hum Reprod 2002;8:1053-64.
22. Andersson K.E. Pharmacology of penile erection. Pharmacol Rev 2001;53:417-50.
23. Filippi S, Marini M, Vannelli GB, et al. Effects of hypoxia on Endothelin-1 sensitivity in the Corpus cavernosum. Mol Hum Reprod 2003;9:765-774.
24. Hall SM, Davie N, Klein N, et al. Endothelin receptor expression in IPAH: effect of bosentan and epoprostenol treatment. Eur Respir J 2011;38:851-860.
25. Karakeci A, Firdolas F, Ozan T, et al. Second pathways in the pathophysiology of ischemic priapism and treatment alternatives.
26. Urology 2013;82:625-629.
27. Bialecki ES, Bridges KR. Sildenafil relieves priapism in patients with sickle cell disease. Am J Med 2002;113:252.
28. Burnett AL, Bivalacqua TJ, Champion HC, et al. Feasibility of the use of phosphodiesterase type 5 inhibitors in a pharmacologic prevention program for recurrent priapism. J Sex Med 2006;3:1077-84.
29. Bivalacqua TJ, Musicki B, Champion HC, Burnett AL. Phosphodiesterase type 5 inhibitor therapy for priapism. In: Carson CC III, Kirby RS, Goldstein I, Wyllie MG, eds. Textbook of erectile dysfunction. 2nd edn. New York: Informa Healthcare 2009:428-433.
30. Burnett AL, Bivalacqua TJ, Champion HC, et al. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology 2006;67:1043-1048.
31. Broderick GA, Kadioglu A, Bivalacqua TJ, et al. Priapism: Pathogenesis, epidemiology, and management. J Sex Med 2010;7:476-500.
32. Beuzard Y. Transgenic mouse models of sickle cell disease. Curr Opin Hematol 1996;3:150-155.
33. Trudel M, De Paepe ME, Chrétien N, et al. Sickle cell disease of transgenic SAD mice. Blood 1994;84:3189-3197.
34. Champion HC, Bivalacqua TJ, Takimoto E, et al. hosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA 2005;102:1661-1666.