Phosphodiesterase type 5 inhibitors in treatment of lower urinary tract dysfunctions

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Abstract


The article provides a review of current data on the pharmacological and pathogenetic principles of the use of selective type 5 PDE inhibitors in patients with lower urinary tract dysfunctions. The mechanisms of the therapeutic action of these drugs for various urinary tract dysfunctions are examined in detail, the leading of which is the improvement of blood circulation and the reduction of ischemia of the pelvic organs.


Full Text

Phosphodiesterase type 5 inhibitors (PDE5Is) have demonstrated efficacy, improved the course, and delayed the progression of endothelial dysfunction. In urological practice, PDE5Is are widely used in the treatment of erectile dysfunction (ED). Furthermore, given the variety of physiological and clinical effects of PDE5Is, the search for new areas of their application continues. PDE5Is might have potential use in the treatment of lower urinary tract dysfunction.

For the first time, new possibilities for the use of PDE5Is were observed when there was an improvement in the urination of patients treated for ED. The first report on this subject was published in 2002 [1] and generated intensive investigation in this area of research. Epidemiological studies confirmed a close relationship between ED and the lower urinary tract symptoms (LUTS). The incidence of LUTS was 72.2% in men with ED, but only 37.7% in men without ED [2]. Similar results were obtained in Russian investigations after interviewing 1225 men aged 22–70 years old [3]. Further studies showed that ED and LUTS had common risk factors along with a high incidence. One of these risk factors mentioned above is metabolic syndrome that clinically presents as diabetes, hypertension, and obesity [4–6].

Most scientists consider pelvic ischemia as a leading pathogenetic factor for pelvic dysfunction. It is also true for both LUTS and ED. Four main general pathophysiological mechanisms underlie their development: deficiencies in the production of nitric oxide (NO) in the pelvic organs, increased sympathetic activity, increased Rho-kinase activity, and the presence of atherosclerosis of the vessels of the pelvis [7, 8].

  1. Deficiencies in the production of NO. The role of NO in providing erectile function is well known. The endothelial isoform of NO synthase in vascular smooth muscle cells activates guanylate cyclase, which leads to an increase in the production of cyclic guanosine monophosphate (cGMP) and, through a cascade of reactions, causes a decrease in intracellular calcium levels and relaxation of cavernous myocytes. Thus, a decrease in NO production is accompanied by impaired erectile function. A deficiency in NO in the urinary tract causes an increase in bladder and urethra smooth muscle tone, as well as an increase in their afferent activity [9, 10]. This is manifested by symptoms of bladder overactivity.
  2. Increased sympathetic activity. Experimental and clinical studies showed that lower urinary tract dysfunction and ED were associated with hypertension and closely related to increased sympathetic activity [11, 12]. Hypertension, as well as hyperglycemia, obesity, and hyperlipidemia, are components of the metabolic syndrome, whose relationship with ED and LUTS has been proven by numerous studies [4, 5].
  3. Increased Rho-kinase activity. Rho-kinase provides Ca2+-independent smooth muscle cell contraction [13]. The Rho-kinase signaling pathway in endothelial cells leads to decreased activity of NO synthase thus preventing smooth muscle relaxation and promoting the development of ED and LUTS [14]. Increased Rho-kinase activity is reported in patients with diabetes and hypertension [15]. In this regard, an increased Rho-kinase activity is considered as one of the connecting mechanisms between ED and LUTS [16].
  4. Atherosclerosis of the vessels of the pelvis. Atherosclerotic vascular disease causes blood circulation impairment and ischemia of pelvic organs and promotes the development of ED and LUTS [17]. Atherosclerotic disease of bladder vessels has been shown experimentally to be accompanied by a decrease in elasticity and expansibility of the bladder wall [18]. Doppler ultrasonography detected a lower cystometric capacity and a higher frequency of urination in cases of more severe vessel atherosclerosis [19]. For pelvic ischemia, bladder filling is associated with a decrease in hemodynamic parameters, and reperfusion after voiding may cause oxidative cell damage. Especially significant reperfusion injuries are pronounced in patients with atherosclerosis of the intravesical vessels [20].

Thus, an impairment of blood flow in the pelvis leading to lower urinary tract ischemia is considered a main pathogenetic factor for lower urinary tract dysfunction. Pelvic ischemia, along with infravesical obstruction and neurological diseases, is proved to be an independent risk factor for bladder overactivity which is one of the components of LUTS [21–23]. Bladder overactivity is a widespread condition that significantly reduces the quality of life of patients [24, 25]. The microcirculation in the bladder wall was studied in patients with bladder overactivity in the urology clinic of Academician I.P. Pavlov First Saint Petersburg State Medical University [26, 27]. The study showed that the severity of microcirculation impairment was correlated with the severity of the symptoms of the disease. Moreover, the degree of arterial blood flow impairment was associated with the severity of urgency, whereas the degree of venous and capillary blood flow impairment was associated with the frequency of urination. The severity of microcirculation impairment in the bladder wall depended on the degree of pelvic sensation and correlated with hypertension, ischemic heart disease, and chronic constipation. The obtained data led to speculation about the drugs that improved the microcirculation in the bladder wall in patients with bladder overactivity [26, 27].

Kershen et al. [28] showed that during bladder filling, the circulation in the bladder worsened, this was related to compression of the intradetrusor vessels, and after voiding, the circulation increased. Acute urinary retention with mechanical compression of the intramural vessels due to increased infravesical pressure causes persistent vasospasm and detrusor ischemia that subsequently leads to bladder dysfunction [29]. An experimental study performed by Vince et al. [30] confirmed that with an increase in intravesicular pressure during the filling phase, a decrease in bladder perfusion occurred. Involuntary bladder contractions because of detrusor overactivity as well as increased intravesicular pressure because of infravesical obstruction and reduced expansibility of the bladder wall because of fibrosis may lead to a blood flow impairment in the bladder wall. With morphological changes in the detrusor associated with ischemia, damage to intramural nerves occurs, which leads to detrusor denervation, and worsening of bladder dysfunction. Thus, ischemia of the bladder wall is a main pathogenetic mechanism primarily for the bladder overactivity. Then, morphological changes and detrusor decompensation increase and proceed to underactivity. A similar sequence of events was identified earlier in the study of changes in the structure and function of the urinary tract in patients with diabetes complicated by diabetic cystopathy [31–33].

Since ED and LUTS have common pathogenetic mechanisms, the expectations that the treatment methods should also be similar are justifiable. In this regard, the use of PDE5Is fully fits into this concept. The main therapeutic mechanisms of the efficacy of PDE5Is for LUTS are smooth muscle relaxation of the detrusor and urethra and improvement in lower urinary tract circulation. Both effects are due to the therapeutic action of PDE5Is. These drugs inhibit PDE5 that is found in smooth muscle cells of the bladder, urethra, prostate, and vascular wall. PDE5 promotes the conversion of cGMP back to guanosine triphosphate that leads to a decrease in protein kinase G activity, the arrest of NO-dependent signaling, an increase in intracellular calcium, a decrease in potassium concentration, the phosphorylation of actin and myosin, and results in the constriction of urinary tract smooth muscle cells and vasoconstriction [34]. Thus, by increasing the cGMP level in smooth muscle cells, PDE5Is decrease the tone in the lower urinary tract and promote intramural vasodilation, both of which improve blood circulation in the pelvic organs [35, 36]. In experiments, PDE5Is were shown to inhibit Rho-kinase activity, which promoted an improvement in ischemia of the bladder wall [37]. Another mechanism of blood perfusion in the bladder wall is an improvement of blood flow in the vesicular artery. It was established that this artery is characterized by high activity of PDE5, which can be inhibited by tadalafil [36]. An important aspect of the therapeutic action of PDE5Is is the capability to modulate a sensory function of the bladder. A study showed that PDE5Is decreased the mechanosensitive afferent activity of both Aδ- and C-fibers, thereby decreasing bladder sensitivity, an effect that is important for the treatment of patients with overactive bladder [38].

Thus, PDE5Is for the treatment of lower urinary tract dysfunction seem to be pharmacologically and pathogenetically reasonable [10, 21]. Currently, several forms of PDE are known, some of them hydrolase predominately cyclic adenosine monophosphate, others – cGMP. Messenger-RNAs of PDE type 1A, 1B, 2A, 4A, 4B, 5A, 7A, 8A, and 9A are found in bladder tissue. Most of them inhibit the hydrolysis of cGMP [39]. To date, PDE5Is are the most widely used in clinical practice. Using immunohistochemical studies and by evaluating the expression of mRNA with a quantitative polymerase chain reaction, PDE5 was found in the muscle fibers and blood vessels in the bladder, urethra, and prostate gland. The highest concentration of PDE5 was detected in the bladder, and the lowest was in the prostate [40].

The efficacy of PDE5Is was confirmed by a substantial number of experimental and clinical studies. In an experimental study, the capability of PDE5Is to decrease the contractility and afferent activity of the bladder was shown in animals with neurogenic bladder overactivity associated with spinal cord injury [41]. The evidence demonstrating the ability of PDE5Is to improve bladder circulation was also experimentally obtained [42].

Clinical trials proved the efficacy of PDE5Is in the treatment of LUTS either alone or in combination with other drugs [43–46]. For example, improvement in symptoms is observed in week 1 of therapy with tadalafil at a dose of 5 mg per day with a statistically significant decrease in the total international prostate symptom score (IPSS) by 22%–37% [45]. However, despite the significant improvement in IPSS and IIEF (international index of erectile function), PDE5Is had no significant effect on the maximum urinary flow rate compared with placebo [46–48]. An important direction for the clinical application of PDE5Is is their use in combination with other drugs. A meta-analysis of five randomized clinical trials (two studies of tadalafil 20 mg, two studies of sildenafil 25 mg, and one of vardenafil 20 mg) showed that the combined therapy significantly improved scores on the IPSS (–1.8) and IIEF (+3.6), and increased the maximum urinary flow (+1.5 ml/sec) compared to alpha-blocker monotherapy [49].

Sivkov et al. [50] reported results of the study, where the PDE5I vardenafil (20 mg per day) was compared with M-anticholinergic medication solifenacin (5 mg per day) in men with bladder overactivity and ED. The duration of therapy was eight weeks. All patients noted an improvement. In four out of 26 patients in the vardenafil group, symptoms of bladder overactivity resolved completely. There was a positive dynamic in urodynamic parameters in this group. After treatment, an infused mean volume at which the onset of the first involuntary detrusor contraction (IDC) occurred was increased significantly from 93.9 ± 14.4 to 146.4 ± 13 cm H2O. The number of IDCs decreased from 2.5 ± 1.1 to 1.9 ± 0.9 cm H2O. The range of maximum IDCs decreased from 21.1 ± 10 to 15.3 ± 9.4 cm H2O, and the maximum cystometric capacity increased from 150.2 ± 31.5 to 224.7 ± 40.1 ml. In the solifenacin group, all patients also reported an improvement regarding urinary frequency, urgent urination, and the number of episodes of urge urinary incontinence. The authors concluded that PDE5Is were appropriate as both monotherapy and combined therapy in patients with bladder overactivity [50].

In patients with benign prostatic hyperplasia, PDE5I is one of the pathogenetic methods of treatment. PDE5Is have the following main mechanisms of therapeutic action in men with LUTS associated with benign prostatic hyperplasia: decrease in the muscular tone of the prostate and bladder, decrease of prostate cell proliferation, a decrease of inflammation in the prostate, and inhibition of bladder afferent activity [51, 52].

PDE5Is seem to be pathogenetically reasonable for the treatment of patients with underactive bladder. This condition is manifested by voiding difficulty, absence or significant decrease of urinate desire, and an increase in postvoid residual urine volume. Occasionally, there may be no urination [53]. An urodynamic study revealed decreased detrusor contractility and bladder sensitivity. The reasons for bladder underactivity are variable. Most often, it develops as a complication of neurological diseases (peripheral neuropathies, lumbosacral spinal cord injuries) or as a result of decompensation of the bladder in patients with infravesical obstruction, or because of diseases that directly lead to damage to the bladder vessels, such as diabetes. In addition, regardless of the reason, ischemia of the bladder wall plays an important, and in some cases, a crucial role in the development and progression of bladder underactivity. Thus, hypoxia of the bladder wall is accompanied by the loss of nerve endings (bladder denervation), a decrease in smooth muscle cells, and the proliferation of collagen fibers that frequently render the condition permanent [53, 54].

A special form of bladder dysfunction is distinguished – detrusor overactivity with impaired contractility. Several researchers consider it a transitional state from hyperactivity to underactivity of the detrusor [55]. This condition is manifested by symptoms of underactive bladder (frequent urination, urgent urination, and urge urinary incontinence). In addition, there is urinary difficulty and an increase in postvoid residual urine volume. This means that in the voiding phase, the detrusor does not perform its function in the full range. Such a condition was studied in the experiment and was described for neurologic diseases, bladder outlet obstruction, and diabetes [55–57]. Further progression of this condition leads to “pure” detrusor underactivity.

Gotoh et al. [58] studied the effect of tadalafil on bladder perfusion in an experimental model of diabetic cystopathy with detrusor underactivity. Animals received tadalafil at a dose of 2 mg/kg per day for seven days. The treatment with PDE5Is promoted an increase in parameters specific for microcirculation in the bladder wall and suggested that PDE5Is might improve bladder perfusion [58]. Another study in an experimental model of neurogenic detrusor underactivity showed that an improvement in bladder perfusion promoted an increase in detrusor contractility, and a decrease in bladder capacity and postvoid residual urine volume [59].

Improvement in bladder voiding for detrusor underactivity is the main goal of therapy. This goal can be achieved either by increasing the contractile capability of the detrusor, or by reducing the urethral resistance. Since the relaxation of smooth myocytes of the bladder outlet area is mediated by nitric oxide, PDE5Is in such patients can also have a therapeutic effect. In a recent study, this concept was proved experimentally [60]. In a model of neurogenic detrusor underactivity with detrusor sphincter dyssynergia, tadalafil was associated with a significant decrease in postvoid residual urine volume and an increase in voiding efficiency with no increase in detrusor contractility. Thus, the efficacy of the treatment was achieved by the relaxation of the urethra during voiding that led to an increase in voiding efficiency [60].

Thus, in patients with lower urinary tract dysfunction, PDE5Is are pathogenetically reasonable, and studies showed their clinical efficiency. To date, tadalafil is a single PDE5I recommended by the European Association of Urology and approved by the FDA for LUTS treatment. However, there are clinical trials that proved another PDE5Is to be effective for lower urinary tract dysfunction treatment. Currently, besides tadalafil, there are six commercially available oral PDE5Is, including sildenafil, vardenafil, udenafil, and mirodenafil.

About the authors

Igor V. Kuzmin

Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of the Russian Federation

Author for correspondence.
Email: kuzminigor@mail.ru
https://www.ooorou.ru/ru/users/kuzminigor-mail-ru.html

Russian Federation, Saint Petersburg

Doctor of Medical Science, Professor, Urology Department

Abdul Kh. Ajub

Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of the Russian Federation

Email: hammad.315@yandex.ru

Russian Federation, Saint Petersburg

Postgraduate

Margarita N. Slesarevskaya

Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of the Russian Federation

Email: mns-1971@yandex.ru

Russian Federation, Saint Petersburg

Candidate of Medical Science, Senior Research Fellow, Urology Research Center

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