Review – Sexual MedicineUpdate on Phosphodiesterase (PDE) Isoenzymes as Pharmacologic Targets in Urology: Present and Future☆
Introduction
The cyclic nucleotide monophosphates (cNMPs) cAMP and cGMP are important intracellular regulators of several processes, including smooth muscle motility, electrolyte homeostasis, neuroendocrine signals and retinal phototransduction [1], [2]. Nitric oxide (NO) is a crucial mediator of smooth muscle relaxation of the corpus cavernosum. It is also suggested to be involved in the regulation of smooth muscle tonus of the outflow region, prostate, clitoris and vagina, and to modify neurotransmission in the urogenital region [3], [4], [5]. NO interacts with the soluble guanylate cyclase (sGC) in the cell cytoplasm and increases the rate of conversion of GTP into cGMP. The structurally related particulate GC (pGC) extends in an extracellular domain to which natriuretic peptides bind and subsequently can accumulate intracellular cGMP [2]. The molecular mechanism underlying, for example, the control of smooth muscle contractility by cAMP is similar, and includes interactions with cyclic nucleotide-regulated protein kinases, ion channels and PDEs. cNMPs are synthesized following a physiologic signal (e.g., the release of NO from nonadrenergic, noncholinergic nerve terminals or activation of specific G-protein-coupled receptors on the outer cell surface) from the corresponding nucleoside triphosphate by the activity of adenylyl and guanylyl cyclases. This increase in cAMP or cGMP triggers a signal transduction cascade that encompasses the activation of cyclic nucleotide-dependent protein kinases A and G, subsequent phosphorylation of the actin-myosin system, as well as Ca2+ channels and adenosine triphosphate-driven Ca2+ pumps located in the outer cell membrane or the membrane of the sarcoplasmatic reticulum. This cascade leads to a reduction in cytosolic Ca2+ and, finally, to smooth muscle relaxation. cNMPs are degraded by PDEs, a heterogenous group of hydrolytic enzymes. It is because of their central role in smooth muscle tone regulation that PDEs have become an attractive target for drug development. PDEs are classified according to their preference or affinity for cAMP and/or cGMP, kinetic parameters of cNMP hydrolysis, relative sensitivity to inhibition by various compounds, allosteric regulation by other molecules and chromatographic behaviour on anion exchange columns (Fig. 1).
Eleven families of PDE isoenzymes can be distinguished: Ca2+/calmodulin-stimulated PDE (phosphodiesterase type 1 [PDE1]), cGMP-stimulated PDE (PDE2), cGMP-inhibited PDE (PDE3), cAMP-specific PDE (PDE4), cGMP-specific PDE (PDE5) and the cGMP-binding, cGMP-specific PDE of mammalian rods and cones (PDE6). While PDE7 (cAMP-high affinity) and PDE8 (3-isobutyl-1-methylxanthine [IBMX]-insensitive) have preferred selectivity for cAMP, PDE9 exclusively degrades cGMP. PDE 10 and 11 can inactivate both cAMP and cGMP [6], [7], [8], [9], [10], [11]. Some of these isoenzyme families contain more than one gene (isogenes), and some genes are alternatively spliced so that, to date, more than 50 isoenzymes or variants have been described [12], [13], [14], [15]. Some PDE genes are also variably transcripted in different tissues. For example, PDE2 is predominantly found in vascular smooth muscle. Expression of PDE5 in the corpus cavernosum and the cGMP-mediated relaxation of the cavernous smooth muscle during sexual stimuli have made inhibition of this enzyme a clinical benefit in the management of erectile dysfunction (ED). Phosphodiesterase 7 is abundant in skeletal muscle and is also present in human kidney, brain, and pancreas. Although expressed in other tissues, high levels of PDE8, PDE10 and PDE11 are found in the testis, and PDE9 is expressed in intestinal smooth muscle, skeletal muscle and brain [13], [15]. To date, 6 of these 11 isoenzymes (PDE 1, 2, 3, 4, 5 and 11) have been proven to be of pharmacologic importance. Since the distribution and functional significance of PDE isoenzymes vary in different tissues, isoenzyme-selective inhibitors have the potential to exert specific effects on the target tissue. Although mammalian tissues express several members of PDE families or more than one variant of an individual family, there are numerous examples in which an individual PDE is predominantly found in a specific localization (Table 1).
Section snippets
Male erectile dysfunction
The discovery of the importance for relaxation of human cavernous tissue of the NO and cGMP pathway is a landmark for the development of the “modern” pharmacology of ED [16], [17]. It has led to the identification of certain drugs that can elevate intracellular levels of cGMP. Among these agents are the NO donors sodium nitroprusside, nitroglycerine and linsidomine (SIN-1), and selective inhibitors of PDE5 [18], [19]. Further reports of PDE5 as one crucial regulator of the intracellular amount
Premature ejaculation
Besides erectile dysfunction, premature ejaculation (PE) is another very common sexual disorder among males. PE might be primary or secondary to other underlying diseases. The pharmacotherapy of PE has been primarily focused on behavioural therapy, topical anaesthetics, tricyclic antidepressants and selective serotonin reuptake inhibitors. Nevertheless, an approved treatment is not yet available. Therefore, the community of pharmacologists and physicians is aiming to set up new pathophysiologic
Diseases of the prostate: benign prostatic syndrome and prostate cancer
The so-called benign prostatic syndrome (BPS) represents a major health care problem in westernized countries. BPS comprises obstructive and irritative symptoms (lower urinary tract symptomatology [LUTS]), as well as benign prostatic enlargement (BPE) with variable degrees of bladder outlet obstruction [67], [68]. It is estimated that approximately 50% of men older than 50 years have moderate to severe symptoms arising from LUTS and that 25% of these seek medical attention for relief of
Bladder overactivity
Anticholinergic drugs are currently the therapy of choice to treat urgency and urge incontinence [89]. Nevertheless, until now, muscarinic receptor blockers acting exclusively on detrusor smooth muscle are not available. Moreover, the unstable detrusor seems to be regulated in part by noncholinergic mechanisms. These factors may explain the common side-effects and the limited clinical efficacy of anticholinergics. The development of new drugs with novel mechanisms of action for the treatment of
Urinary stone disease
Urinary stone disease is an indication in which pharmacologic relaxation of ureteral smooth muscle would present an attractive therapeutic alternative. In the case of an uncomplicated renal or ureteral concrement, the intravenous administration of analgesics is the most effective way to relieve pain [95]. With respect to the potential beneficial effect of ureteral relaxation on stone passage, spasmolytic agents, such as phentolamine and orciprenaline, have been shown to dilate the ureteral
Female sexual dysfunction
Female sexual dysfunction (FSD) is evolving as a new and exciting topic in urology. FSD is supposed to be age related and highly prevalent, affecting approximately 30–50% of women in westernized countries [99], [100]. Because of the development of successful treatments for male ED, FSD is now also receiving increased awareness among clinicians and pharmacologists. Although FSD is a condition involving anatomic, physiologic, psychologic and medical components, it is without doubt that the normal
Gene-based strategies targeting PDE isoenzymes
Instead of abandoning the activity of a PDE isoenzyme by using selective inhibitors, downregulation of the expression of a respective PDE protein has also been discussed. This approach is an attractive alternative, since no cross-reactions with PDEs in the same or other tissues are expected to occur because of the unique sequences of exons and mRNA specific for PDE isoforms [116]. It is known that twice as much mRNA encoding for PDE5A is expressed in the human corpus cavernosum than in
Conclusion
On the basis of the knowledge of the physiologic mechanisms regulating the male and female urogenital tract, the use of selective PDE inhibitors has been suggested a logical approach for the treatment of various urologic diseases. The increased scientific awareness in this field and the unending charge to conceive first-line treatments demonstrating advanced and superior efficacy to that of previous options offer a promising future for the use of PDE inhibitors in the therapy of diseases of the
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Unraveling the structure and function of CdcPDE: A novel phosphodiesterase from Crotalus durissus collilineatus snake venom
2021, International Journal of Biological MacromoleculesEffect of chronic Sildenafil treatment on the prostate of C57Bl/6 mice
2014, Tissue and CellCitation Excerpt :Phosphodiesterases (PDEs) are enzymes that are widely distributed in the body, hydrolyzing cyclic nucleotides, cAMP and cGMP to their inactive 5′-monofosfatos forms. Experimental studies using immunohistochemical methods have detected PDE isoenzymes 4, 5 and 11 in the fibromuscular prostatic stroma, as well as in the glandular structures of the transition zone of the prostate, suggesting that PDE enzymes play an important role in dynamic activity, secretory function and prostatic tissue proliferation (Ückert et al., 2006a,b). The PDE-5 enzyme is responsible for the hydrolysis of the GMPc, which restores GMP levels.
Tadalafil inhibits the cAMP stimulated glucose output in the rat liver
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2012, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation Excerpt :More specific, the drug sildefanil (Viagra) is a selective and potent inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) that degrades cGMP in the corpus cavernosum. Consequently, an increase in cGMP concentration and smooth muscle relaxation (vasodilation) is the result, leading to an increase of blood flow in the tissues of the penis, causing an erection [17–19]. Therefore cGMP could serve as a mechanistic biomarker for the pharmaceutical inhibition of PDE's by specific chemical entities [20,21].
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