Inhibitors of phosphodiesterase-5 (PDE5) are a class of drug that were originally developed as anti-ischaemic agents based on their ability to overexpress the nitric oxide (NO) pathway pursued via cyclic guanosine monophosphate (cGMP) signalling. Since the effects on myocardial oxygen consumption determinants were found to be less relevant than expected,1 they were not considered to have a real advantage over commonly used nitrates. However, later on the clinical applicability of the enhanced NO/cGMP pathway in terms of inhibiting PDE5 activity was felt to be more relevant than previously thought. Accordingly, over the last few years the use of PDE5 inhibitors has been expanded to the therapeutic management of some cardiovascular disorders, including heart failure (HF).
PDE5 comprises an enzyme superfamily with 11 subfamilies that hydrolyse the phosphodiester bond of cGMP and cyclic adenosine monophosphate (cAMP) to form the inactive 5’-GMP and 5’-AMP. PDEs have been characterised on the basis of amino acid sequence, substrate specificity, pharmacological properties and allosteric regulation. Within these families more than 40 isoforms are expressed either by different genes or as an expression of the same gene through alternative splicing.2 The substrate specificities include enzymes that are specific for cyclic AMP hydrolysis, enzymes for cyclic GMP hydrolysis3 and those that hydrolyse both. The importance of PDEs as regulators of signalling is evident from their development as drug targets in diseases such as asthma and obstructive pulmonary disease, cardiovascular diseases such as HF and atherosclerotic peripheral disease, neurological disorders and erectile dysfunction.
Among all PDEs, PDE5, which is inhibited by sildenafil and other inhibitors of clinical use, has been widely investigated.2 Three PDE5 isoforms have been described: PDE5 A1, A2 and A3.4 The PDE5 A1 and A2 isoforms are expressed in several tissues including the brain, lungs, heart, kidneys, bladder, prostate, urethra, penis, uterus and skeletal muscle. The A3 isoform is located in tissues having cardiac or smooth muscle constituents, such as the heart, bladder, prostate, urethra, penis, uterus and skeletal muscle.
Sildenafil (Viagra), vardenafil (Levitra) and tadanafil (Cialis) are the three specific PDE5 inhibitors in current clinical use,5 which, despite similar although not identical mechanisms of action and structural similarity, present some significant differences regarding potency and selectivity. For instance, Vardenafil is 32-fold more potent than sildenafil in inhibiting PDE5:6 in the rat aorta, vardenafil but not sildenafil or tadalafil affects serum calcium (Ca++) handling to produce relaxation in addition to the typical increase of cGMP mediated by PDE5 inhibition.7
In experimental and clinical cardiology, sildenafil is the more extensively investigated agent. Sildenafil, although very selective for PDE5, shows some cross-reactivity with PDE6, which is predominant in photoreceptors8 and may transiently disturb colour vision perception in individuals taking high doses of sildenafil.9 Another cross-reactivity is that found with PDE11, which may be responsible for the development of back pain and myalgia as side effects of tadanafil due to the low selectivity of the compound for PDE5 over PDE11.
Sildenafil shows a rapid onset of activity, and plasma half-life is four hours.10–12 Empirical testing shows that the duration of action of sildenafil may reach 12 hours.13 The results of numerous studies consistently suggest that more commonly used drugs do not disturb the pharmacokinetics of sildenafil, and that the compound is well tolerated and does not interfere with the physiological effects of most drugs.
Use of Phosphodiesterase-5 Inhibition in Heart Failure
Vasoconstriction is a pathophysiological hallmark of HF, which involves the systemic and the pulmonary circulation. A defective NO pathway is central to HF syndromes. Among strategies to enhance in vivo NO-based mechanisms, inhibition of PDE514 has attracted interest as a potential therapeutic tool in HF prompted by experience accumulated in patients with pulmonary vascular hypertension.15
Pulmonary Circulation and Gas Diffusion
Given the high selectivity of PDE5 for the pulmonary microvessels, lung haemodynamics has reasonably been regarded as the primary target of PDE5 inhibitors in HF. The potential favourable therapeutic properties of PDE5 inhibition on pulmonary vascular remodelling and lung microvessel over-reactivity to vasoconstrictor stimuli has been the rationale for a number of studies.16–19
Similar to what has been described for idiopathic pulmonary hypertension, studies performed by Guazzi et al.16 and by Lewis et al.17 in patients with chronic HF and secondary pulmonary hypertension have shown that oral acute sildenafil 50mg lowers the pulmonary vascular pressure and resistance without significantly affecting the systemic arterial and wedge pulmonary pressures. The response of cardiac output is variable and in part related to the severity of the disease. The resistance-lowering effect of sildenafil in the pulmonary circulation at rest is also evident during exercise. Recently, the same authors have reported that the PDE5 inhibitor maintains the same efficacy during long-term prescription.18,19
An additional finding by Guazzi et al.16 is that sildenafil improves the lung diffusion capacity for carbon monoxide (DLCO) by more than 10% in patients with CHF through a selective increase of the DM component (alveolar capillary membrane conductance) of DLCO without affecting the pulmonary capillary volume of blood (Vc) available for gas exchange (the other component of DLCO). This is significant because not only does it prove the ability of PDE5 inhibition to influence one of the lung functional shortcomings in CHF, but also because it suggests that a defective NO/cGMP pathway is involved in the shortcoming.
Systemic Haemodynamics and Endothelial Function
Impaired vasomotion and endothelial dysfunction are hallmarks of HF that increase systemic vascular resistance (SVR). Hirata et al.20 investigated the acute effects of oral sildenafil 50mg on SVR, large artery stiffness and wave reflection as major determinants of left ventricular ejection impedance. They found a parallel decrease of these variables with an improvement in cardiac performance. A similar effect on aortic pressure augmentation index has been observed in patients with hypertensive heart disease.21
Due to these effects on large-conduit systemic arteries, sildenafil has been suggested to have an indication also in the management of systemic hypertension, especially of the isolated systolic form. Oliver et al.22 demonstrated that prolonged (three-month) administration of sildenafil 50mg three times a day to patients with high blood pressure induced a modulation of the arterial wave reflection and lowered systolic and diastolic ambulatory pressure by an average of 8 and 6mmHg, respectively.
A number of studies suggest that sildenafil may also improve endothelial dysfunction due to HF.23,24 In a report in which sildenafil was tested in patients with stable HF at doses of 12.5, 25 and 50mg, flow-mediated dilatation in the forearm circulation increased in a dose-dependent effect, and the lowest effective dose was shown to be 25mg. An additional endothelial effect of sildenafil 50mg on top of the angiotensin-converting enzyme (ACE) inhibitor ramipril was also demonstrated in patients with heart failure by Hryniewicz et al.25 Interestingly, according to observations obtained in a canine model of cardiac failure, sildenafil produced haemodynamic effects reminiscent of those produced by B-type natriuretic peptides26 and exerted a cumulative influence on pulmonary blood pressure elevation. Considering that resistance to the natriuretic peptide in HF is in part related to increased PDE5 activity, a combined approach and an additional therapeutic role for PDE5 inhibition may be prospectively investigated.
PDE5 has been shown to prevent the development of cardiac hypertrophy, ischaemia-reperfusion injury and excessive adrenergic stimulation; PDE5 inhibition can prevent these protective activities. Sildenafil reverses hypertrophy27,28 through a cGMP-mediated effect in hypertrophic and failing hearts by sustained exposition to pressure overload. In a rat model of isoproterenol-induced cardiac hypertrophy, an inverse correlation was consistently evident between cGMP heart content and severity of hypertrophy.29 However, cGMP catabolism regulates cardiac adrenergic stimulation.30 Sildenafil also exhibits a direct protective property against myocite apoptosis,28 an effect also observed in a model of cardiac dysfunction secondary to doxorubicin cardiotoxicity.31
Benefits of sildenafil on experimental post-myocardial infarction (MI) ventricular remodelling have recently been reported by several authors.32,33 In particular, recent findings by Salloum et al. obtained in a murine model document that sildenafil modulates reactive post-MI hypertrophy and attenuates late adverse remodelling through myocite savage and reduced apoptotic cell death.33 There is also recent evidence that PDE5 is highly expressed in the hypertrophied human right ventricle and that acute PDE5 inhibition improves contractility.34
In the human heart, PDE5 is basically involved in the contractile response to β-adrenergic receptor stimulation35 and sildenafil blunts the inotropic response. Acute sildenafil also reduces the cardiac norepinephrine spillover, which seemingly results from an inhibition of the sympathetic outflow to the heart.36
Exercise Performance and Gas Exchange Analysis
Studies have consistently found that peak oxygen consumption (VO2) is improved by sildenafil in heart failure,16,17 and several mechanisms may be involved in this effect: the increased NO availability may promote the alveolar capillary membrane gas conductance improvement;16 the cGMP-mediated lowering effect of pulmonary arterial pressure and vascular resistance decreases the right ventricular afterload and improves right ventricular output and lung perfusion; and a better right ventricular function and a diminished peripheral resistance that improve left ventricular output and systemic perfusion.
Another relevant effect observed during exercise is a modulation of the excessive ventilation (VE) response to exercise in relation to carbon dioxide (CO2) output (VE/VCO2) commonly seen in patients with HF.37,38 Reasons for VE inefficiency may be a lung VE/perfusion mismatch or an overstimulation of the centres that control ventilation due to an excessive responsiveness of the reflexogenic areas of the cardiovascular system, or of the exercising muscle metaboreceptors.
The favourable effect of sildenafil on VE/VCO2 slope has been demonstrated both acutely and in the long term,16–19 possibly through a decrease of waste ventilation, as prospected by a reduction of the dead space to tidal volume ratio and by a facilitated alveolar–capillary membrane gas conductance.16,17,19 On the other hand, abnormal skeletal muscle signalling due to stimulation by muscle metabolic by-products (ergoreflex) is becoming a prominent concept in our quest to understand and treat HF. It is conceivable that muscle reflex contribution to VE can be reduced by improving endothelial function and upregulating muscle perfusion. Specifically, it has been proved that sildenafil intake can produce an endothelium-mediated attenuation of the peripheral stimulus to hyperventilation and breathlessness, and this effect results in an improved exercise ventilatory efficiency.19,39
Conclusions and Perspectives
An impaired NO pathway is typical of HF patients and contributes to several abnormalities in cardiac and vascular function. PDE5 inhibition is a new therapeutic strategy for overexpressing NO signalling by increasing cGMP availability and progressively accumulating evidence to support the use of this class of compounds across HF populations. However, initial promising perspectives await confirmation by large-scale randomised controlled trials.