Abstract and Introduction

Abstract

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.

Introduction

Erectile dysfunction (ED) is a common medical condition linked both to endothelial dysfunction^[1-13] as well as multiple other comorbid conditions.^[14-17] Historically, the treatment for ED has been limited to a selected group of specialists, namely urologists and sexual therapists. In 1998, the Food and Drug Administration (FDA) approved the first phosphodiesterase-5 inhibitors (PDE-5i) (sildenafil, Viagra) for oral ED therapy. The ensuing avalanche of research and interest in sexual dysfunction has been transferred this once 'private condition' from the exclusive domain of the urologist into the laps of numerous medical disciplines and demonstrated the close connection between endothelial dysfunction and ED as well as the potential signaling of ED as an early marker for cardiovascular conditions.^[18] To date, PDE-5i are the most widely prescribed oral agents for ED treatment and Viagra is one of the most frequently sold drugs in the world. Specialists of all varieties are increasingly encountering patients seeking therapy for sexual dysfunction. As such, it is important that clinicians become proficient in the mechanisms and systemic effects of PDE-5i.

PDE-5i are considered first-line therapy for ED. Sildenafil is the most commonly prescribed oral agent for ED, and has earned a satisfactory efficacy safety profile in nearly all patient cohorts. Tadalafil (Cialis) and vardenafil (Levitra) emerged in the European Union and in the US in 2003 and 2004, respectively. All three agents share many pharmacological and clinical characteristics, while still maintaining some unique features.

Mechanism of Action of PDE-5i

PDE-5i act as selective inhibitors of cyclic guanosine monophosphate (cGMP)-specific PDE-5 enzyme which results in increased levels of cGMP and nitric oxide (NO).^[19] Sexual stimulation causes local release of NO and with the inhibition of PDE-5, there is increased levels of cGMP in the corpus cavernosum. The increase levels of cGMP lead to reduced intracellular calcium levels, thereby producing smooth muscle relaxation in corpus cavernosum and an increase in blood flow in erectile tissue.^[20] Studies in vitro have shown that sildenafil is preferentially selective for PDE-5, but not exclusive of other phosphodiesterase enzymes.^[1,21]

The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole among several others) as well as the nonspecific CYP inhibitor cimetidine can be associated with increased plasma levels of PDE-5i.^[22-26] Whether this is clinically relevant is controversial. While the three PDE-5i have similar mechanism of actions, differences exist in properties, especially in duration of action and bioavailability ( Table 1 ).

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine citrate. It was not originally developed for the treatment of ED. Rather, sildenafil was the result of a discovery program that began in 1985 at Pfizer's European Research headquarters in Sandwich, UK, aimed at developing a selective inhibitor of PDE-5 to augment the NO/cGMP pathway for the treatment of angina pectoris in patients with coronary artery disease (CAD). The drug was patented in 1996, approved for use in ED by the FDA on 27 March, 1998.

Vardenafil (Levitra) was approved by FDA for the treatment of ED on 20 August 2003. Vardenafil appears to be as effective as sildenafil, as supported by a trial of 805 men aged 57–78 years with ED of various etiologies. Vardenafil was more effective than placebo for improving penetration (64–80% versus 50%, respectively) and maintenance of erections (50–67% versus 32%, respectively).^[27]

Tadalafil (Cialis) was approved by the FDA in November 2003 for the treatment of ED. Tadalafil has a longer duration of action (t? 17.5 h). This distinguishes the drug clinically from sildenafil and vardenafil, offering the theoretical advantage of more 'spontaneity' with sexual relations. Its efficacy was proved by an integrated analysis of randomized trials in 1112 men with ED: 75% of intercourse attempts were successful in the tadalafil patients compared with only 32% with placebo.^[28]

Effect of PDE-5i use on ED

Several clinical trials have established efficacy and safety of PDE-5i in men with ED of all etiologies, ages and ethnic populations. Those with the most limited responses included patients with diabetes, ischemic heart disease, radical prostatectomy, and age over 65 years. Although onset of action can vary from 15 to 60 min, it is important to counsel patients to expect optimal response at 60 min after administration.^[29] Since its introduction, PDE-5i have been extensively studied, specially its effect on various subgroups of patients such as diabetics, older men, and patients with CAD.

Effect of PDE-5i for ED in Patients With Diabetes Mellitus

A multicenter, double-blind, placebo-controlled study assessed the effectiveness and safety of tadalafil (10 or 20 mg) in 216 men with mild to severe ED and type 1 or type 2 diabetes. The study showed tadalafil improved erectile function in men with diabetes regardless of diabetes type, current diabetic therapy and initial level of glycemic control or the presence of microvascular complications.^[30] Another study assessing efficacy and patient satisfaction on sildenafil in diabetic patients with ED showed a significant improvement of ED. Hence, both studies suggested the efficacy of PDE-5i in patients with coexistent diabetes.^[31]

Effect of PDE-5i for ED in Older Patients

PDE-5i has been proven to be beneficial in the elderly population (>65 years) with ED. This has been successfully demonstrated in a study involving patients more than 70 years of age. Sildenafil demonstrated 69% of successful intercourse as compared to 22% with placebo.^[32] Analysis of data from a phase 2 vardenafil trial (to assess the differences in erectile response to vardenafil between younger patients (<45 years) and older patients (>65 years)) suggested improvement in erectile function in both groups, suggesting PDE-5i as representing an effective ED therapy also in the elderly,^[33] with similar side effects when compared to younger men.

Effect in Patients With Ischemic Heart Disease

Patients with ED and coexisting ischemic heart disease have shown significant improvement in erectile function by using PDE-5i. This has been shown by a meta-analysis of 357 patients with ischemic heart disease enrolled in 11 randomized double-blind, placebo-controlled trials on sildenafil. In these patients mean scores on ability to achieve and maintain erection were significantly higher for sildenafil-treated patients than for the placebo group. Mean scores for all five International Index for Erectile Function (IIEF) domains were also significantly higher.^[34]

Effect of PDE-5i use on the Lung

In a normal human lung, NO secretion by pulmonary endothelium plays an important role in lung physiology.^[31] It is involved in the special capacity of the vasculature to adapt to local changes in blood flow, maintenance of normal pulmonary vascular tone, permeability,^[35] and the modulation of tissue resistance to oxygen transfer (from the alveolus to its uptake by hemoglobin). Pulmonary hypertension may reflect an increase in left heart filling pressure in the presence of normal pulmonary vascular resistance, pulmonary vascular or parenchymal disease with an elevation in pulmonary vascular resistance, or a combination of these initiating factors. The majority of data available in patients with primary pulmonary hypertension implicates an imbalance between endothelial-derived vasodilating factors such as prostaglandin I2 (PGI2), NO, and vasoconstricting mediators such as endothelin-1 and thromboxane A2, producing a net effect of precapillary pulmonary hypertension. Secondary pulmonary hypertension in most cases is attributed to various causes such as heart failure (HF), acute respiratory distress syndrome (ARDS), postlung transplantation, and pulmonary embolism.

Recent studies demonstrated promising therapeutic potential of PDE-5i in pulmonary hypertension, which is due to the fact that the gene encoding PDE-5 is highly expressed in the lung.^[36] Guazzi et al.^[37] showed a reduction in pulmonary systolic (21.8%) and diastolic (20.7%) arterial pressures and in arteriolar resistance (45.1%) after sildenafil administration in patients with stable HF (in NYHA classes II–III), without significant changes in cardiac index and wedge pulmonary pressure. In all but one patient, there was an increase in diffusion capacity. The authors concluded that PDE-5 inhibition attenuated (secondary) pulmonary hypertension by lowering arteriolar resistance, facilitating alveolar gas exchange, and improving overall exercise performance and ventilation efficiency in patients with HF. Lepore et al.^[38] studied the hemodynamic effects of 50 mg of sildenafil alone and in combination with inhaled NO in nine patients with severe pulmonary hypertension and showed shown that the combination of oxygen and NO with sildenafil reduced pulmonary vascular resistance more than oxygen and NO alone. Michelakis et al.^[39] also showed a decrease in pulmonary vascular resistance with the combined use of PDE-5i and NO in 13 patients with pulmonary hypertension. To date, there is only few data available on the effects of vardenafil and tadalafil on pulmonary vasculature. A case report by Palmieri et al.^[40] described a 72-year-old woman with pulmonary hypertension who showed marked improvement in functional status (NYHA classification), arterial oxygenation and a decrease in systolic pulmonary hypertension after using tadalafil for 6 months. The reduction of pulmonary arteriolar resistance and pressure in HF patients by concomitant use of NO and PDE-5i is expected, moreover since a defective NO release can be found in pulmonary hypertension that facilitates pulmonary vasoconstriction. Interestingly, in these patients sildenafil also significantly improved brachial artery flow-mediated endothelial function, which was not observed in controls. Overall, PDE-5i also promoted a favorable reduction of the alveolar-capillary membrane resistance to gas exchange. Hence because of the vasodilator properties of PDE-5i in pulmonary vasculature, it has proven to be beneficial also when used in conjunction with prostaglandin inhibitors in the treatment of pulmonary hypertension.^[41,42,43]

Effect of PDE-5i use on the Heart

ED shares several modifiable risk factors with cardiovascular disease including atherosclerosis, hypertension, dyslipidemia, diabetes mellitus, smoking, obesity, and sedentary lifestyle.^[15-18] As PDE-5 is found in smooth muscles of the systemic arteries and veins throughout the body, use of PDE-5i has been associated with various cardiovascular effects.

Effect on Cardiac Contractility

There is no conclusive evidence of the effects of PDE-5i on cardiac contractility. Corbin et al.^[44] demonstrated that sildenafil does not have any direct inotropic effect on segments from dog (or human) heart. Similarly, in patients with severe CAD or stable ischemic heart disease, no or only small decreases in cardiac output were observed after either oral or intravenous (i.v.) sildenafil administration.^[45] Similar results were shown in in vitro studies. In humans, however, in a randomized double-blinded placebo-controlled study by Borlaug et al.^[46] involving 35 healthy volunteers, it has been shown that sildenafil suppressed β-adrenergic stimulated systolic function (but had only little effects under resting conditions). In summary, more studies are needed to assess the effects of PDE-5i on cardiac contractility, since in particular the effects of vardenafil and tadalafil on cardiac contractility are unclear, yet.

Effects on Central Hemodynamics and Peripheral Vasculature

Sildenafil is known to have both arterio-dilating and veno-dilating properties on the peripheral vasculature. This can be explained by increased cGMP levels in vascular smooth muscle. In a randomized controlled study in patients with known CAD (or at high risk for CAD), the use of sildenafil had no effect on heart rate, cardiac index or exercise-induced wall motion score index.^[45] In another study involving eight CAD patients with stable angina, i.v. sildenafil reduced systemic and pulmonary arterial pressures and cardiac output by 8, 25, and 7%, respectively, consistent with mixed arterial and venous vaso-dilating effects.^[47]

A number of studies have assessed the effects of PDE-5i on blood pressure and heart rate. Small, transient decreases in systolic and diastolic blood pressure (-8/-5 mm Hg in supine position) occurred 1–2 h after oral sildenafil (congruent with the time to peak serum concentration). Interestingly, the decreases in blood pressure were neither age- nor dose-related. The lack of a clear dose–response might be explained by the degree of inhibition of PDE-5.^[8] No consistent orthostatic effects and no significant differences in blood pressure response between the young and elderly were found. Sildenafil's blood pressure-lowering effect is only modest and therefore unlikely to trigger a reflex heart rate response. Indeed, a mild sympathetic response directly to the vasculature may be responsible for the maintenance of blood pressure without triggering a reflex tachycardia. Mahmud et al.^[47] showed a decrease in both systolic and diastolic blood pressure with no significant changes in heart rate in patients on current antihypertensive medications (either monotherapy or dual therapy using amlodipine, diuretics, angiotensin converting enzyme inhibitors, and/or diltiazem) following sildenafil administration. Similar effects have been shown in patients taking tadalafil and vardenafil for ED. In a study involving the use of 10 or 20 mg tadalafil in healthy patients there was a small but statistically significant reduction in systolic and diastolic pressure without adverse effects on hemodynamics.^[48] In a crossover study comparing sildenafil (50 mg) and vardenafil (10 mg) both agents caused a drop in systolic (sildenafil: 4.7?4.2 mm Hg, vardenafil: 5.4?5.5 mm Hg) and diastolic blood pressures (sildenafil: 4?4.1 mm Hg, vardenafil: 5.0?5.3 mm Hg), with a slight increase in heart rate (sildenafil: 1.2?0.9 beats per minute (b.p.m), vardenafil: 2.4?2.3 beats per minute).^[49]

PDE-5i have been shown to be tolerated with a wide range of concomitant antihypertensive drugs, such as β-adrenergic receptor blockers, calcium channel blockers, and angiotensin converting enzyme inhibitors (ACEi). However, PDE-5i should be used with caution in patients receiving α blocking agents since the combination of both might lead to excessive vasodilatation and hypotension. For tadalafil and vardenafil, the combination with α-blockers has been considered as a precaution. On the other hand, the combination with nitrates or any NO donating agents (such as nitroprusside among a few others) can cause cumulative hypotension that can be life threatening, in particular in patients with CAD and critical stenoses, and therefore is the main contraindication for PDE-5i use.

Effect on Coronary Vasculature

Sildenafil has been shown to selectively increase cGMP in vascular smooth muscles of isolated canine coronary arteries. Concentrations of 10–100 nM demonstrated a dose response, however, further increases in concentration had no effects on cGMP levels. Traverse et al.^[9] studied the effects of sildenafil on coronary blood flow at rest and during exercise in chronically instrumented dogs and found that sildenafil caused an increase in coronary blood flow, suggesting a modest vasodilator activity in coronary resistance vessels. Myocardial hypoperfusion, induced by exercise in the presence of a left anterior descending coronary artery stenosis, was improved by increased coronary blood flow after sildenafil administration. This was achieved at the same distal coronary pressure before and after treatment with sildenafil, suggesting a direct effect on the coronary microvasculature. In a study in humans, Herrmann et al.^[45] demonstrated no change in coronary blood flow but a significant increase in coronary flow reserve in both stenosed and nonstenosed coronary arteries. Sildenafil, in contrast to nitrates, is therefore unlikely to cause a coronary steal phenomenon.

Effects on Patients With HF

Chronic HF is an increasingly common cardiovascular disease with approximately 75% of patients reporting associated ED. The efficacy and safety of PDE-5i in men with HF has been reported by several groups. Bocchi et al.^[50] studied the effects of sildenafil in HF patients and reported an improvement in the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score and the scores for questions regarding the frequency of penetration and the frequency of maintained erections after penetration (IIEF Questionaire) when compared with baseline. Webster et al.^[51] showed a significant improvement in IIEF results in a single-center placebo-controlled fixed-dose crossover trial involving 35 men with HF and ED over a 12-week period. Sildenafil use was also associated with improved quality-of-life scores and amelioration of symptoms of depression when compared with placebo. Katz^[52] described a study to investigate the safety and efficacy of sildenafil in patients with ED and stable HF and observed a significant improvement in erections (74%) and the ability to have intercourse (68%) if compared to a placebo group (18 and 16%, respectively). There is yet no data, however, on the effects of vardenafil and tadalafil in patients with HF.^[53] Hence sildenafil has proven to be efficacious and safe in patients with ED and stable HF.

Effect of PDE-5i use on Other Organ System

Besides erectile tissue, the lung and the heart, PDE-5i have also been known to exert physiological effects on other systems such as platelets and the eyes.

Effects on Platelets

Human platelets contain PDE-5 -2, -3, and -5 ( Table 2 ). Initial data suggested that sildenafil has no direct effects on platelet function, but that it did modestly potentiate the inhibitory effect of the NO-donor sodium nitroprusside on adenosine diphosphate-induced platelet aggregation ex vivo. This is consistent with the requirement for an NO drive for sildenafil to produce its pharmacologic effects.^[44] In a recent study by Dunkern et al.^[54] it was shown that sildenafil potentiated antiplatelet aggregatory effect of NO donors in vitro. The authors also illustrated that sildenafil plus sodium-nitroprusside in low concentrations partially inhibited thrombin-induced release of serotonin, hence eliciting the antisecretory activity of sildenafil. However, because the effects of sildenafil have not been evaluated in patients with bleeding disorders or in patients taking antiplatelet agents such as ticlopidine, clopidogrel, or dipyridamole, caution should be taken if the drug is administered with this concomitant medication.^[55] The effect of vardenafil and tadalafil specifically on platelets has not been well defined. It is suggested, however, that PDE-5i have antiaggregatory effects on platelets, the clinical potential of which has yet to be explored.

Effect on the Gastrointestinal Tract

There is only rare data on the effects of PDE-5i use on the gastrointestinal tract. Studies carried out in animal models have shown an inhibitory effect of PDE-5i on smooth muscles in the gastrointestinal tract. Araujo et al.^[56] showed that sildenafil had an inhibitory effect on rat duodenal contractility in vitro, which was thought to be caused by a myorelaxant and antispasmodic effect on rat duodenal tissue, most likely secondary to intracellular cGMP accumulation. Almost similar results were shown by Zhang et al.^[57] in the esophagus of cats by studying the effects of sildenafil propagation of esophageal contractions and lower esophageal sphincter relaxation. The authors concluded that sildenafil caused a reduced amplitude of esophageal contractions. Additionally, the time period from swallowing to distal esophageal contractions was significantly prolonged in associated with a reduction in lower esophageal sphincter pressure. Moreover, Sarnelli et al.^[58] assessed the role of sildenafil on gastric sensorimotor function and demonstrated that sildenafil increased postprandial gastric volume (and slowed time required to empty liquids), which was thought to be attributed to NO-induced smooth muscle relaxation.

In vitro studies of PDE-5i on human anal sphincter have shown myogenic effects associated with relaxation of the internal anal sphincter.^[59] Altogether, PDE-5 inhibition has been shown to induce smooth muscle relaxation and inhibition of peristalsis by NO-mediated cGMP pathways.

Effect on the Endothelium

It has been suggested that endothelial dysfunction results in decreased endothelial-derived NO production. This may be attributed to a downregulation of the mRNA production for the endothelial enzymes NO synthase and cyclooxygenase, both of which are required for vasodilator properties of the endothelium. Endothelial function has been shown to be altered in patients with HF (ischemic or nonischemic in nature), diabetes mellitus and CAD.^[60] Some animal studies showed beneficial effects of PDE-5i use on the endothelium function in diabetics. For example, Ahn et al.^[61] studied the effect of DA-8159 (PDE-5i) on diabetic rats and demonstrated that chronic administration of PDE-5i attenuated the development of ED. This effect was associated with an improvement in endothelial dysfunction. Interestingly, human studies have also demonstrated that administration of sildenafil might limit myocardial damage induced by prolonged ischemia-reperfusion-induced endothelial dysfunction,^[62] which has been attributed to the opening of ATP-dependant potassium channels. Moreover, tadalafil improved endothelial function in patients with increased cardiovascular risk, an effect that was sustained for at least 2 weeks after discontinuation of the drug.^[63] On the other hand, there are conflicting data on PDE-5i effects in smoking-induced endothelial dysfunction. Dishy et al.^[64] showed that there was no significant change in flow-mediated dilatation of the brachial artery (and in forearm postischemic reactive hyperemia) by PDE-5i in smokers. However, a study by Vlachopoulos et al.^[65] demonstrated that PDE-5i (sildenafil) abrogates the smoking-induced acute decrease in flow-mediated dilatation of the brachial artery. Endothelial dysfunction with impaired endothelium-dependent flow-mediated vasodilatation in patients with HF is partly attributed to hyporesponsiveness of cGMP-mediated vasorelaxation mechanisms in vascular smooth muscle. In a study by Katz et al.,^[66] PDE-5i increased endothelium-dependent, flow-mediated vasodilatation in patients with chronic HF when compared to placebo.

Effect on Visual Function

Sildenafil is approximately 10-fold as potent for PDE-5 compared to PDE-6,^[5,22] an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels. Transient visual abnormalities^[67] such as color-tinged (blue-green) vision, increased perception of light, and blurred vision have been reported in patients taking sildenafil, particularly at high oral doses (>100 mg). In patients with inherited disorders of retinal PDE-6, such as retinitis pigmentosa, sildenafil should be administered with extreme caution. Several case reports published between 2000 and 2005 suggest a temporal association between PDE-5i and nonarteritic anterior ischemic optic neuropathy (NAION) and the obstruction of the cilioretinal artery,^[68] and pupil-sparing third nerve palsy,^[69] associated with the intake of high dosages of sildenafil. Moreover, in May and July 2005, the media reported about individuals who have decided to sue Pfizer because of vision loss caused by NAION that occurred in association with PDE-5i.

NAION is a frequent cause of untreatable, sudden, irreversible vision loss in individuals older than 40 years. The condition is characterized by optic disc edema, frequently associated with nerve fiber layer hemorrhages, an afferent papillary defect and visual field loss that has been reported rarely in men after taking sildenafil or other PDE-5i for ED. An analysis of clinical trial data in more than 13 000 men and on more than 35 000 patient-years of observation in epidemiologic studies, an estimated incidence of 2.8 cases of NAION per 100 000 patient-years of sildenafil exposure was recognized, which is similar to estimates reported in general US population samples (2.52 and 11.8 cases per 100 000 men aged ≥50 years).^[70] Even though individual cases have been reported for all PDE-5i, these recently published data do not suggest an increased incidence of NAION in men who took PDE-5i for ED.

Effect on Cerebral Blood Flow

PDE-5 has also recently been reported to be present in brain tissue, predominantly in the cerebellum, hippocampus and superior cervical ganglion.^[71] PDE-5 has also been shown to be present and active in the guinea-pig basilar artery^[72] and in human cerebral arteries. Kruuse et al.^[72] showed that sildenafil had no vasodilator effects on cerebral arteries, with no effect on cerebral blood flow or blood flow velocity. This fact has been reinforced in a pilot study by Arnavaz et al.^[73] who showed that there was no significant change in blood flow velocity changes of the middle cerebral artery before and after administration of sildenafil. The lack of a dilatory response to sildenafil in cerebral arteries and arterioles in healthy subjects may indicate that cGMP is not accumulated in cerebral smooth muscle or that a compensatory regulatory mechanism effectively decreases cGMP. Another explanation may be that the PDE-5 in smooth muscle cells is a splice variant, which inhibits sildenafil only to a minor degree, but not enough to elicit vasodilatation. No studies have been carried out to assess the effects of vardenafil and tadalafil on cerebral blood flow.

Effects of Chronic PDE-5i use

There is a paucity of data on the long-term effects of chronic PDE-5i use. There is no consensus on the definition of long-term or chronic use, with studies stating it from 4 weeks to 1 year. Few studies in both animal models and in human subjects have assessed the long-term effects of PDE-5i use, mainly indicating long-term beneficial effects with minimal side effects.

Some animal studies have shown beneficial pulmonary and cardiac effects with long-term PDE-5i use. In an animal model Schermuly et al.^[74] studied the chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. At 4 weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Sildenafil, when chronically administered from days 14 to 28, significantly increased plasma cGMP and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. Moreover, the death rate significantly decreased in animals treated with sildenafil. Hence, the authors concluded that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats. In an another animal study^[75] involving long-term sildenafil use for approximately 8 weeks on the effect of doxorubicin-induced cardiomyopathy and cardiotoxicity, it was shown that treatment with clinically relevant doses of sildenafil (0.7 mg/kg) 1 h before doxorubicin administration resulted in cardioprotection from doxorubicin-induced cardiotoxicity. These data also illustrated the capacity of sildenafil in attenuation of cardiomyocyte apoptosis, preservation of myofibrillar integrity, prevention of left ventricular dysfunction, and prevention of ST prolongation consistent with chronic doxorubicin toxicity 8 weeks after the treatments. In a unique study by Takimoto et al.,^[76] the authors showed that blocking the intrinsic catabolism of cGMP with chronic use of oral PDE-5i for 9 weeks (sildenafil) suppressed chamber and myocyte hypertrophy, and improved in vivo cardiac function in mice exposed to chronic pressure overload induced by transverse aortic constriction. The authors also postulated that sildenafil reversed pre-established hypertrophy. However, sildenafil had no effect on hypertrophy if induced by overexpression of calcineurin in vitro or Akt gene in vivo. Based on these interesting findings, PDE-5i might provide new treatment strategies for cardiac hypertrophy and remodeling in the future.

In a study involving the effect of long-term vardenafil treatment on development of fibrotic plaques in a rat model of Peyronie's disease (PD), vardenafil slowed and reversed the early stages of an experimental PD-like plaque in rat, and might have ameliorated a more advanced plaque.^[77] These effects were noted after giving vardenafil for 45 days. No data were found looking at long-term effects of tadalafil in animal models.

A number of studies have been published in human subjects to assess long-term effects of PDE-5i use. A study by Stiebellehner et al.^[78] evaluated long-term sildenafil therapy in patients with pulmonary hypertension in addition to continuous i.v. epoprostenol. The authors demonstrated that chronic use of sildenafil (for 5 months) improved pulmonary hemodynamics and quality-of-life, without major adverse events such as systemic hypotension or decreased arterial oxygenation. In another small study^[79] of 14 patients, with pulmonary hypertension of various etiologies treated with sildenafil, 1 year follow-up was associated with increased exercise tolerance and pulmonary blood flow without changes in pulmonary pressures. Again, no major adverse effects were noted, suggesting clinical safety on chronic use of sildenafil. PDE-5i have also been shown to have favorable effects on chronic thromboembolic pulmonary hypertension that occurs secondary to a progressive increase in lung vascular resistance after remodeling following emboli. This was shown by Ghofrani et al.^[41] in a study of 12 patients with nonoperable, progressive, chronic thromboembolic pulmonary hypertension despite sufficient long-term anticoagulation. Significant improvements in exercise capacity and pulmonary hemodyanmics after 6 months of therapy with oral sildenafil were seen. In a recently published case report,^[80] sildenafil was safely used for 323 days in a 14-month-old child who had undergone cardiac surgery for d-transposition of the great arteries, ventricular septal defect and pulmonary hypertension. The patient was weaned off NO postsurgery and had normal pulmonary pressure postsildenafil use. There were no observed side effects with long-term drug usage.

Only few data are available on cardiac effects of long-term PDE-5i use. In a recently published study by Preston et al.,^[81] 10 HF patients in NYHA classes III–IV were followed after an average course of 12?1.6 months of sildenafil therapy. Six of the 10 patients reported improvement in NYHA functional score by at least one class and nine patients reported improvement in exertional dyspnea. Echocardiograms obtained after two 8 months of initiation of sildenafil therapy showed no change in peak systolic pulmonary artery pressures or right ventricular function. A 6 min walk test improved from 191?46 to 250?50 m (P<0.05).

Chornic tadalafil therapy, on the other hand, has also shown favorable effects on systemic endothelial dysfunction (which is clearly associated with ED).^[10-13] Rosano et al.^[63] noted that chronic therapy with tadalafil improved endothelial function in men with increased cardiovascular risk. In total, 32 patients were randomized to receive tadalafil 20 mg and placebo for 4 weeks. End points of the study were brachial artery flow-mediated dilatation, nitrite/nitrate ratio, and endothelin-1 plasma levels at baseline and at follow-up. At 4 weeks brachial artery flow-mediated dilation was significantly improved. Moreover, compared to the placebo group, the tadalafil group had a net increase in the nitrite/nitrate level and a decrease in endothelin-1 levels, indicating an improvement in endothelial function after chronic use of PDE-5i.

Hemodynamic effects of PDE-5i (tadalafil) administered daily for 26 weeks was assessed in another randomized placebo-controlled study.^[82] At the end of 26 weeks, the mean change in systolic and diastolic blood pressure was similar between two groups suggesting no significant hemodynamic deterioration after chronic use of PDE-5i.

Conclusion

The role of PDE-5i as a treatment modality has been ever expanding since its first approval in 1998. From the initial use in patients with ED, PDE-5i are now indicated for the use in patients with pulmonary hypertension, thereby highlighting its multiorgan beneficial effects. Being a relatively newer drug and associated apprehension on its usage, PDE-5i are not used to their utmost potential and there exists a large realm of the disease world where this drug can prove beneficial. In particular, owing to well-studied effects on vasculature and hemodynamics by PDE-5i, several data exist from experimental as well as human studies regarding efficacy and tolerability. There is, however, lack of data on long-term, chronic PDE-5i use in patients with underlying cardiovascular disorders. So far, long-term PDE-5i in stable patients with or without cardiovascular or pulmonary disorders are promising and have not shown unwanted chronic side effects. Further studies, especially in patients considered at high risk, are warranted.

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Abbreviations: BP, blood pressure; ED, erectile dysfunction; PDE-5i, phosphodiesterase-5 inhibitors.

 

Abbreviation: PDE, phosphodiesterases.

 

Dr. E.R. Schwarz, Division of Cardiology, Cedars Sinai Medical Center and University of California, Los Angeles (UCLA), 8700 Beverly Blvd, Suite 6215, Los Angeles, CA 90048, USA. E-mail: schwarze@cshs.org