Cyclic GMP Phosphodiesterase-5: Target of Sildenafil

Abstract

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. Trends Biochem. Sci. 1997; 22: 307-312Abstract Full Text PDF PubMed Scopus (348) Google Scholar, 5Hofmann F. Dostmann W. Keilbach A. Landgraf W. Ruth P. Biochim. Biophys. Acta. 1992; 1135: 51-60Crossref PubMed Scopus (104) Google Scholar, 6Furchgott R.F. Vanhoutte P.M. FASEB J. 1989; 3: 2007-2018Crossref PubMed Scopus (1665) Google Scholar, 7Garbers D.L. Lowe D.G. J. Biol. Chem. 1994; 269: 30741-30744Abstract Full Text PDF PubMed Google Scholar, 8Arnold W.P. Mittal C.K. Katsuki S. Murad F. Proc. Natl. Acad. Sci. U. S. A. 1977; 74: 3203-3207Crossref PubMed Scopus (1174) Google Scholar, 9Hobbs A.J. Ignarro L.J. Methods Enzymol. 1996; 269: 134-148Crossref PubMed Google Scholar, 10Moro M.A. Russel R.J. Cellek S. Lizasoain I. Su Y. Darley-Usmar V.M. Radomski M.W. Moncada S. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1480-1485Crossref PubMed Scopus (419) Google Scholar). Intracellular receptors for cGMP include cGMP-dependent protein kinases (PKG), cyclic nucleotide-gated channels, and cGMP-binding PDEs; cGMP may also cross-activate cAMP pathways by binding to cAMP-binding sites on cAMP receptors such as cAMP-dependent protein kinases (PKA) (11Jiang H. Colbran J.L. Francis S.H. Corbin J.D. J. Biol. Chem. 1992; 267: 1015-1019Abstract Full Text PDF PubMed Google Scholar). Tissue cGMP levels are determined by a balance between the activities of the guanylyl cyclases that catalyze formation of cGMP from GTP and the cyclic nucleotide PDEs that catalyze the breakdown of cGMP (Fig. 1). The combination of a stimulator of guanylyl cyclase and a cGMP PDE inhibitor such as sildenafil produces synergistic enhancement of tissue cGMP levels (12Jeremy J.Y. Ballard S.A. Naylor A.M. Miller M.A. Angelini G.D. Br. J. Urol. 1997; 79: 958-963Crossref PubMed Google Scholar). PDEs were first detected by Sutherland and co-workers (13Rall T.W. Sutherland E.W. J. Biol. Chem. 1958; 232: 1065-1076Abstract Full Text PDF PubMed Google Scholar, 14Butcher R.W. Sutherland E.W. J. Biol. Chem. 1962; 237: 1244-1250Abstract Full Text PDF PubMed Google Scholar). The superfamily of PDEs is subdivided into two major classes, class I and class II (15Charbonneau H. Beavo J. Houslay M.D. Cyclic Nucleotide Phosphodiesterases: Structure, Regulation and Drug Action. John Wiley & Sons, Inc., New York1990: 267-296Google Scholar), which have no recognizable sequence similarity. Class I includes all known mammalian PDEs and is comprised of at least 10 identified families that are products of separate genes (16Beavo J.A. Conti M. Heaslip R.J. Mol. Pharmacol. 1994; 46: 399-405PubMed Google Scholar, 17Conti 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. Chem. 1997; 272: 6823-6826Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, 19Houslay M.D. Adv. Enzyme Regul. 1995; 35: 303-338Crossref PubMed Scopus (34) Google Scholar, 20Bolger G.B. Cell. Signal. 1994; 6: 851-859Crossref PubMed Scopus (128) Google Scholar,