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Molecular Mechanisms That Could Contribute to Prolonged Effectiveness of PDE5 Inhibitors to Improve Erectile Function

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Molecular Mechanisms That Could Contribute to Prolonged Effectiveness of PDE5 Inhibitors to Improve Erectile Function International Journal of Impotence Research (2008) 20, 333–342 & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00 www.nature.com/ijir REVIEW Molecular mechanisms that could contribute to prolonged effectiveness of PDE5 inhibitors to improve erectile function SH Francis, GZ Morris and JD Corbin Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA Cyclic guanosine monophosphate (cGMP) in penile vascular smooth muscle cells (VSMC) plays a key role in promoting penile erection. Phosphodiesterase-5 (PDE5) in VSMC breaks down cGMP to counter this effect. Sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis), treatments for erectile dysfunction, inhibit PDE5 action. Many men with erectile dysfunction have improved erectile function after plasma inhibitor concentration falls below therapeutic levels. Maximum effect plus onset and duration of action of inhibitor determines its efficacy. The rate and extent of cellular drug accumulation and efflux of drug from smooth muscle cells plus persistence of drug effects in these cell impact these parameters. We propose possible molecular mechanisms that could account for prolonged action of PDE5 inhibitors including (1) persistence of biochemical effects after inhibitor is cleared from cells, and (2) retention of drug in VSMC beyond plasma clearance. International Journal of Impotence Research (2008) 20, 333–342; doi:10.1038/ijir.2008.4; published online 17 April 2008 Keywords: PDE5 inhibitors; erectile dysfunction; prolonged drug action; sildenafil; vardenafil; tadalafil Introduction which is abundant in VSMC, specifically breaks down cGMP to the inactive 50-GMP at its catalytic The central role of cyclic guanosine monophosphate site and also binds cGMP at nonhydrolytic allosteric (cGMP) signaling in the erectogenic response of sites in its regulatory domain;8–10 cGMP binding to the penile tissues to sexual stimuli is now well allosteric sites increases activity of the catalytic site.11–13 established.1,2 Nitric oxide (NO) released from both The cellular cGMP level in corpus cavernosum is nonadrenergic noncholinergic nerve terminals and primarily dictated by the balance between the rate of endothelial cells of the penis activates a NO- cGMP synthesis by guanylyl cyclases and cGMP sensitive guanylyl cyclase to increase conversion breakdown by PDE5. Under healthy physiological of GTP to cGMP (Figure 1). Cyclic GMP binds with conditions, cGMP elevation in penile tissues in high affinity to cGMP-dependent protein kinase response to sexual stimulation is sufficient to cause (PKG) and activates this enzyme to cause phosphor- selective vasodilatation of the penile vasculature ylation of numerous cellular proteins that are and engorgement of the organ. This pathway can involved in modulating the level of cellular calcium be compromised in a number of ways including and calcium sensitivity of calcium-regulated path- decreased blood flow due to structural and functional ways.3–5 The consequences of this effect, that is, deterioration of the peripheral vascular bed and/or cGMP activation of PKG activity, are central to the nerves, insufficient production of NO by neurons contractile state of penile vascular smooth muscle and/or endothelium, excessive breakdown of cGMP cells (VSMC) and the erectile response to sexual by PDE5, decreased compliance of the VSMC and stimuli (Figure 1).1,6,7 Phosphodiesterase-5 (PDE5), penile connective tissue or a combination of these processes. As can be seen in Figure 1, deficiencies in several other sites of the signaling pathway are also possible. In some of these scenarios, cGMP elevation in Correspondence: Professor SH Francis, Department of the VSMC may not be adequate to provide for a Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 21st and Garland, sufficient degree of penile tumescence thereby resulting Nashville, TN 37232-0615, USA. in erectile dysfunction (ED). However, inhibition of E-mail: [email protected] PDE5 activity would favor greater accumulation Received 21 December 2007; revised 30 January 2008; of cGMP and facilitate the erectile response in many accepted 30 January 2008; published online 17 April 2008 of these conditions.7,14–16 Prolonged effect of PDE5 inhibitors SH Francis et al 334 EROTIC STIMULUS PDE5 INHIBITOR I settings, and in some instances use of a different dosing regimen, may mandate closer consideration NEURONS & ENDOTHELIUM of the pharmacokinetics of these medications and cG cG cG cG characteristics reported by patients currently using GTP PDE5 the products. PDE5 inhibitors other than sildenafil, cGMP 5’-GMP vardenafil and tadalafil have also either already NITRIC GUANYLYL OXIDE CYCLASE been launched or are in clinical trials in world cG 19 PKG ATP markets. The pharmacokinetics of sildenafil, vardenafil P-PROTEINS PROTEINS and tadalafil have been well documented overall. PI The onset of action, maximum effect and duration of Phosphatases action of PDE5 inhibitors are among many pharma- Lower Ca++ & Desensitize to Ca++ cokinetic factors that must be considered for optimal efficacy of the medications as well as ease and safety Smooth Muscle Relaxation of use by patients. Among many such factors, the Penile Erection rate of accumulation, extent of accumulation and rate of efflux of drug in cells will impact these Figure 1 Cartoon depiction of cyclic guanosine monophosphate (cGMP)-signaling pathway in smooth muscle cell in penile parameters. There are now numerous reports that vasculature. Nitric oxide (NO) released from nonadrenergic many individuals who use PDE5 inhibitor medica- noncholinergic nerve terminals in the penis and endothelial cells tions experience an improvement in the erectile lining the vasculature in response to erotic stimuli diffuses into response long after the plasma level of the respective the smooth muscle cell where it activates an NO-sensitive drug is below what is considered to be a therapeutic guanylyl cyclase causing increased synthesis of cGMP (shown 20–24 as CG in the white circle) from GTP. Cyclic GMP is broken down level. In this report, we will discuss molecular at the catalytic site of phosphodiesterase-5 (PDE5) shown as the mechanisms that could account for prolonged action open V in the black oval and binds to allosteric sites in the of PDE5 inhibitors. regulatory domain of PDE5 (shown on a different portion of the Sildenafil, vardenafil, and tadalafil have high black oval). Cyclic GMP binds to and activates cGMP-dependent ¼ 4, 0.1–0.4 and 2 nM, protein kinase (PKG) shown as the black rectangle, thereby inhibitory affinity (IC50 promoting a cascade of phosphorylation events resulting in respectively) for the catalytic site of PDE5 compared lowering of intracellular calcium, desensitization to calcium to the B600- to 25 000-fold lower affinity of B 25–28 signaling, smooth muscle relaxation and penile erection. Phos- the natural substrate, cGMP (Km 2.5 mM). phorylation of proteins by PKG is counterbalanced by phospho- PDE5-selective inhibitors compete with cGMP for protein phosphatases, which dephosphorylate the proteins. PDE5 access to the catalytic site and are therefore inhibitors (shown as I in the white diamond), such as sildenafil 12,28,29 (Viagra), vardenafil (Levitra) and tadalafil (Cialis), have high known as ‘competitive inhibitors’. The three affinity for the PDE5 catalytic site thereby blocking cGMP access inhibitors do not interact with the nonhydrolytic to the site and fostering cGMP accumulation. The allosteric allosteric cGMP-binding sites on PDE5 (Figure 1).29 cGMP-binding sites of PDE5 and PKG are distinct from each other and from the catalytic site of PDE5, as indicated by the different shapes of the sites that interact with cGMP so that PDE5 inhibitors interact only with the PDE5 catalytic site. Prolonged action of PDE5 inhibitors in treatment of ED Use of PDE5 inhibitors to treat disease By all accounts, efficacy of action of sildenafil, PDE5 is the target of three potent PDE5-selective vardenafil or tadalafil to enhance the erectile inhibitors (sildenafil, (Viagra), vardenafil (Levitra) response appears to compare well. The time (Tmax) and tadalafil (Cialis)), which are commercially required to reach maximum plasma concentration available in many countries as oral treatment for (Cmax) and the time of onset of action vary slightly ED.17 Sildenafil (marketed as Revatio) has also been with tadalafil being slightly slower than sildenafil or approved in the United States and Europe as an oral vardenafil. However, the drugs differ substantially treatment of pulmonary arterial hypertension; the in the rate of clearance from plasma; t1 of plasma 2 three drugs are currently being investigated for clearance is B4 h for sildenafil or vardenafil potential use in treatment of a number of other compared to 18 h for tadalafil. Effect of sildenafil medical problems including cardiac hypertrophy or vardenafil in men is optimum at B0.5–1 h, which associated with heart failure, Raynaud’s disease, approximates the time of peak plasma concentration premature ejaculation, priapism, Peyronie’s disease, (Cmax). Plasma concentration of these drugs wanes recovery from stroke, cardiac reperfusion injury, with t1 of B4–5 h so that plasma drug level would be 2 intermittent claudication, benign prostate syndrome low after 12 h (B13% of Cmax). However, studies and other lower urinary tract symptoms, overactive indicate that men still have facilitated erections 12 h bladder,
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