Cyclic GMP Phosphodiesterase-5: Target of Sildenafil (1999)

The advent of the medication, sildenafil, 1Tradename VIAGRA™. 1Tradename VIAGRA™. for treatment of male impotence has attracted widespread attention. This agent potently inhibits a cGMP-binding cGMP-specific phosphodiesterase (PDE5). 2The abbreviations used are: PDE, 3′:5′-cyclic nucleotide phosphodiesterase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; IBMX, 3-isobutyl-1-methylxanthine 2The abbreviations used are: PDE, 3′:5′-cyclic nucleotide phosphodiesterase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; IBMX, 3-isobutyl-1-methylxanthine PDE5 is particularly abundant in smooth muscle, which is enriched in other components of the cGMP signaling cascade. The characteristics of PDE5, its relationship to other PDEs, its role in cGMP signaling, and its involvement in the efficacious action of sildenafil on corpus cavernosum and vascular smooth muscle resulting in penile erection are the subjects of this review. Cyclic GMP has emerged recently as a principal focus in signal transduction. Much of this attention has derived from the fact that most of the non-lytic physiological effects of nitric oxide (Fig.1) and all of the characterized effects of natriuretic peptides and guanylins are mediated by cGMP. In addition to the classical regulatory roles ascribed to cGMP such as stimulation of smooth muscle relaxation, neutrophil degranulation, inhibition of platelet aggregation, and initiation of visual signal transduction, numerous other physiological roles have recently been uncovered (1Schultz K.D. Schultz K. Schultz G. Nature. 1977; 265: 750-751Crossref PubMed Scopus (333) Google Scholar, 2Lincoln T.M. Cornwell T.L. FASEB J. 1993; 7: 328-338Crossref PubMed Scopus (539) Google Scholar, 3Francis S.H. Corbin J.D. Murad F. Cyclic GMP: Synthesis, Metabolism and Function. Academic Press, Orlando, FL1993: 115-170Google Scholar, 4Lohmann S.M. Vaandrager A.B. Smolenski A. Walter U. de Jonge H.R. 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Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). The kinetic properties of catalysis are consistent with a random order mechanism with respect to cyclic nucleotide and the divalent cation(s) that are required for catalysis (32Srivastava D. Fox D.A. Hurwitz R.L. Biochem. J. 1995; 308: 653-658Crossref PubMed Scopus (23) Google Scholar). The catalytic domains of all known mammalian PDEs contain two sequences (HX 3HX n(E/D)) arranged in tandem, each of which resembles the single Zn2+-binding site of metalloendoproteases such as thermolysin (31Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). PDE5 specifically binds Zn2+, and the catalytic activities of PDE4, PDE5, and PDE6 are supported by submicromolar concentrations of Zn2+ (31Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. 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Chem. 1957; 229: 351-361Abstract Full Text PDF PubMed Google Scholar), in the late 1950s, was the first to realize that at least part of the mechanism(s) whereby caffeine enhanced the effect of glucagon, a stimulator of adenylyl cyclase, on cAMP accumulation and glycogenolysis in liver involved inhibition of cAMP PDE activity. Since that time chemists have synthesized thousands of PDE inhibitors, including the widely used 3-isobutyl-1-methylxanthine (IBMX). Many of these compounds, as well as caffeine, are non-selective and inhibit many of the PDE families. One important advance in PDE research has been the discovery/design of family-specific inhibitors such as the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil. Precise modulation of PDE function in cells is critical for maintaining cyclic nucleotide levels within a narrow rate-limiting range of concentrations. Increases in cGMP of 2–4-fold above the basal level will usually produce a maximum physiological response. There are three general schemes by which PDEs are regulated: (a) regulation by substrate availability, such as by stimulation of PDE activity by mass action after elevation of cyclic nucleotide levels or by alteration in the rate of hydrolysis of one cyclic nucleotide because of competition by another, which with of the specificity PDEs PDE2, regulation by that signaling for in stimulation of activity by E. Belfrage P. Manganiello V.C. J. Biol. Chem. 1997; 272: 6823-6826Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar), stimulation of PDE6 activity by the A. I. M.W. P. J. Biol. Chem. 1980; 255: Full Text PDF PubMed Google Scholar), which PDE6 with this or stimulation of activity by with such as by of PDE3, or PDE4 by after cAMP elevation M. Nemoz G. Sette C. Vicini E. Endocr. Rev. 1995; 16: 370-389Crossref PubMed Scopus (316) Google Scholar, 18Degerman E. Belfrage P. Manganiello V.C. J. Biol. 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Chem. 1996; 6: Scopus Google Scholar). is a and inhibitor of the PDE5 and is highly for this PDE with other known PDE families S.A. C.J. K. M.E. Naylor A.M. J. Urol. 1998; PubMed Scopus Google Scholar). In with sildenafil to its in that the enhanced the penile response. The that sildenafil specifically on penile and well on the general which is not at this One is that which is for sildenafil a specific of nitric oxide in the which produce a in cGMP in this PDE5 inhibitor cGMP breakdown and with nitric oxide to cGMP and penile smooth muscle This synergistic which is to to some in vascular the is the that with the of sildenafil. sildenafil has been a treatment for male impotence and may for some as well K. I. A. A. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar). The most effects and of that are with sildenafil are also to from PDE5 in are to be by inhibition of the PDE6 with other PDE families this is to PDE5, and the inhibition of PDE6 by sildenafil is that for PDE5 S.A. C.J. K. M.E. Naylor A.M. J. Urol. 1998; PubMed Scopus Google Scholar). It is that and specific PDE5 inhibitors or of the other components of the cGMP will be in the to as well as other that smooth muscle Ballard and for are to and for into the of cyclic caffeine, and also and for