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Kelso et al. Meyera, A. Sevko, M. Ramacher et al. Yildirim, Y. Ersoy, F. Ercan et al. Zhao, L. Zhang, G. Lian et al. View at: Google Scholar P. Giralt, A. Molinero, J. Hidalgo, and A. Kigerl, J. Gensel, D. Ankeny, J. Alexander, D. Donnelly, and P. Raposo, A. Nunes, R. Luna, S. Semple, T. Kossmann, and M. Pizanis, J. Heckmann, D. Wendt, K. However, at least 11 families of PDE have been identified in mammals 6 , 7 , 8 , 9 Figure 2 , Table 1. The crossreactivity of PDE inhibitors can be attributed largely to similarities of their homologous catalytic domain.
Some, like PDE5, have two identical subunits homodimers , and some, like PDE6, have two different subunits heterodimers. The PDEs also differ in the nature of the regulatory domain of the enzyme and in the role of phosphorylation. In all cases, the catalytic domain is located toward the carboxyl terminus, and the regulatory domain is located toward the amino terminus. A PDE5 monomeric fragment retains the essential catalytic features of the dimeric, full-length enzyme. For example, in PDE1, calcium binding regulates the enzyme.
Phosphorylation is important for some, including PDE5. Occupation of the allosteric binding site by cGMP alters the conformation of PDE5, which exposes a phosphorylation site serine in the bovine enzyme, serine in the human enzyme.
Blockade of this negative feedback mechanism by occupation of the catalytic site is partly responsible for the effect of PDE5 inhibitors on penile erection. Each PDE5 inhibitor is thought to exhibit the same mechanism, but this has not been established.
Several negative feedback mechanisms come into play to lower the level of cGMP when it is elevated. Increased degradation occurs simply by mass action effect ie, increased substrate availability for PDE5. This results in even greater degradation of cGMP.
Finally, increased binding of cGMP to the allosteric site stimulates cGMP degradation by the catalytic site of PDE5 and further increases phosphorylation of this enzyme.
In conclusion, specific molecular and pharmacologic properties endow individual PDE5 inhibitors with unique characteristics. Owing to these distinctions, selective PDE5 inhibitors hold promise for innovative pharmacologic applications.
However, important questions about the properties and function of PDE inhibitors still need to be answered. For example:. Is clearance of PDE5 inhibitors from smooth muscle cells delayed by the tight binding of these inhibitors to PDE5 in the cells? Boolell M et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.
Int J Impot Res ; 8 : 47— CAS Google Scholar. Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol ; 78 : — Rajfer J et al. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med ; : 90— Trigo-Rocha F et al. Intracellular mechanism of penile erection in monkeys. Neurourol Urodyn ; 13 : 71— Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro.
J Urol ; : — Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev ; 75 : — Fisher DA et al. Biochem Biophys Res Commun ; : — Nitric Oxide NO is released with sexual stimulation from nerve endings and endothelial cells in the spongy erectile tissue, the corpus cavernosum of the penis.
It is the latter that sildenafil acts upon. Men who suffer from erectile dysfunction often produce too little amounts of NO. This means that the small amount of cGMP they produce is broken down at the same rate and therefore doesn't have the time to accumulate and cause a prolonged vasodilation effect. Sildenafil works by inhibiting the enzyme PDE5 by occupying its active site. This means that cGMP is not hydrolysed as fast and this allows the smooth muscle to relax.
Sildenafil is a potent and highly selective inhibitor of PDE5. If viewed in cross section, the glans of the penis reveal that the penis consists of three tube-like projections of spongy tissue, the corpus spongiosum, located ventrally and the paired corpi cavernosi located dorsally. In each of the latter is the deep artery of the penis which carries blood over the length of the penis into the open channels that make up the corpus cavernosum.
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