Objective: The following study was performed to evaluate the importance of phosphodiesterases 3A (PDE3A) and 5A (PDE5A) for the regulation of penile smooth muscle tone. Furthermore, indications of side effects of specific inhibitors in certain tissues as well as of a possible relation between the level of PDE3A and PDE5A gene expression and erectile dysfunction should have been deduced from the results obtained.Methods: Total ribonucleic acid was isolated from different human tissues (urogenital tract, gastrointestinal tract, cardiovascular system and central nervous system) and subjected to RTPCR analysis and Northern blotting using primers and probes specific for PDE3A and PDE5A.Results: As shown by RT–PCR and Northern blotting, PDE3A and PDE5A mRNAs exhibit a distinct distribution throughout the tissues examined but were 2–fold higher in cavernous tissue than in all other tissues investigated. However, there were no significant differences in the levels of gene expression between the two subgroups of patients.Conclusions: Very high expression levels of PDE3A and PDE5A in human cavernous tissue underscore the physiological importance of these enzymes for the regulation of penile erection, emphasizing their therapeutical and pharmacological relevance. The distribution pattern of the mRNA for the isoenzymes PDE3A and PDE5A may explain the pharmacological effects as well as the side effects of milrinone and sidenafil.

1.
Beavo JA, Reifsnyder DH: Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci 1990;11:150–155.
2.
Bentley JK, Beavo JA: Regulation and function of cyclic nucleotides. Curr Opin Cell Biol 1992;4:233–240.
3.
Hall IP: Isoenzyme–selective phosphodiesterase inhibitors: Potential clinical uses. Br J Clin Pharmacol 1993;35:1–7.
4.
Burns F, Zhao AZ, Beavo JA: Cyclic nucleotide phosphodiesterases: Gene complexity, regulation by phosphorylation, and physiological implications. Adv Pharmacol 1996;36:29– 48.
5.
Dousa TP: Cyclic 3′,5′–nucleotide phospho– diesterase isozymes in cell biology and pathophysiology of the kidney. Kindey Int 1999;55: 29–62.
6.
Stief CG, Noack T, Anderson KE: Signal transduction in cavernous smooth muscle. World J Urol 1997;15:27–31.
7.
Taher A, Meyer M, Stief CG, Jonas U, Forssmann WG: Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. World J Urol 1997;15:32–35.
8.
Stief CG, Taher A, Truss M, öckert S, Meyer M, Schultz–Knappe P, Forssmann WG, Jonas U: Die Phosphodiesterase–Isoenzyme des humanen Corpus cavernosum penis und deren funktionelle Bedeutung. Aktuel Urol 1995;26: 22–24.
9.
Boolell M, Allen MJ, Ballard SA, Gepi–Attee S, Muirhead GJ, Naylor AM, Osterloh ICH, Gingell C: Sildenafil: An orally active type 5 cyclic GMP–specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1997;8:47–52.
10.
Meacci E, Taira M, Moos JRM, Smith CJ, Movesesian A, Degermann E, Belfrage P, Manganiello V: Molecular cloning and expression of human myocardial cGMP–inhibited cAMP phosphodiesterase. Proc Natl Acad Sci USA 1992;89:3721–3725.
11.
Cheung PP, Xu H, McLaughlin MM, Ghazaleh FA, Livi GP, Colman RW: Human platelet cGI–PDE: Expression in yeast and localization of the catalytic domain by deletion mutagenesis. Blood 1996;88:1321–1329.
12.
Tang KM, Jang EK, Haslam RJ: Expression and mutagenesis of the catalytic domain of cGMP–inhibited phosphodiesterase (PDE3) cloned from human platelets. Biochem J 1997; 323:217–224.
13.
Miki T, Taira M, Hockman S, Shimada F, Lieman J, Napolitano M, Ward D, Taira M, Makino H, Manganiello VC: Characterization of the cDNA and gene encoding human PDE3B, the cGIP1 isoform of the human cyclic GMPinhibited cyclic nucleotide phosphodiesterase family. Genomics 1996;36:476–485.
14.
Stoclet JC, Keravis T, Komas N, Lugnier C: Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiovascular diseases. Exp Opin Invest Drugs 1995;4:1081–1100.
15.
Manganiello VC, Taira M, Degermann E, Belfrage P: Type III cGMP–inhibited cyclic nucleotide phosphodiesterases. Cell Signal 1995; 1:445–455.
16.
McAllister–Lucas LM, Sonnenburg WK, Kadlecek A, Seger D, Le Trong H, Colbran JL, Thomas MK, Walsh KA, Francis SH, Corbin JD, Beavo JA: The structure of a bovine lung cGMP–binding, cGMP–specific phosphodiesterase deduced from a cDNA clone. J Biol Chem 1993;268:22863–22873.
17.
Turko IV, Francis SH, Corbin JD: Potential roles of conserved amino acids in the catalytic domain of the cGMP–binding cGMP–specific phosphodiesterase (PDE5). J Biol Chem 1998; 273:6460–6466.
18.
Yanaka N, Kotera J, Ohtsuka A, Akatsuka H, Imai Y, Michibata H, Fujishige K, Kawai E, Takebayashi SI, Okumura K, Omori K: Expression, structure and chromosomal localization of the human cGMP–binding cGMP–specific phosphodiesterase PDE5A gene. Eur J Biochem 1998;255:391–399.
19.
Lugnier C, Schoeffter P, Le BA, Strouthou E, Stoclet JC: Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat. Biochem Pharmacol 1986;35:1743–1751.
20.
Stief CG, öckert S, Becker AJ, Truss MC, Jonas U: The effect of the specific phosphodiesterase inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 1998; 159:1390–1393.
21.
Boolell M, Gepi–Attee S, Gingell JC, Allen MJ: Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996; 78:257–261.
22.
Chomczynski P, Sacchi N: Single–step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 1987;162:156–159.
23.
Sanger F, Nicklen S, Coulson AR: DNA sequencing with chain–terminating inhibitors. Proc Natl Acad Sci USA 1977;74:5463–5467.
24.
Bourguignon JJ, Desaubry PR, Wermuth CG, Lugnier C: 9–Benzyladenines: Potent and selective cAMP phosphodiesterase inhibitors. J Med Chem 1997;40:1768–1770.
25.
Rulten SL, Dapling JL, Lanfa SC, Steel J, Turay P, Paulson R: Isolation of human phosphodiesterase–5 cDNA and in situ analysis of its expression in human corpus cavernosum. J Urol 1998;159:92A.
26.
Goldstein I, Lue TF, Padma–Nathan H, Rosen R, Steers W, Wicke PA: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397–1403.
27.
Boolell M, Allen MJ, Ballard SA, Gepi–Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C: Sildenafil: An orally active type 5 cyclic GMP–specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996;8:47–51.
28.
Steers W: Meta–analysis of the efficacy of sildenafil in the treatment of severe erectile dysfunction. J Urol 1998;159:238A.
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