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. 2017 Mar 23;175(2):223–231. doi: 10.1111/bph.13749

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Sevil Korkmaz‐Icöz 1,✉, Tamás Radovits 2, Gábor Szabó 1
PMCID: PMC5758391  PMID: 28213937

Abstract

Phosphodiesterase type 5 (PDE5) selectively hydrolyses the second messenger cGMP into 5′‐GMP, thereby regulating its intracellular concentrations. Dysregulation of the cGMP‐dependent pathway plays a significant role in various cardiovascular diseases. Therefore, its modulation by drugs, such as PDE5 inhibitors, may represent an effective therapeutic approach. There are currently four PDE5 inhibitors available for the treatment of erectile dysfunction: sildenafil, vardenafil, tadalafil and avanafil. Sildenafil and tadalafil have also received Food and Drug Administration approval for the treatment of pulmonary arterial hypertension. This review summarizes the pharmacological aspects and clinical potential of PDE5 inhibition for the treatment of myocardial ischaemia/reperfusion injury and heart failure.

Linked Articles

This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc

Abbreviations

Bcl 2

B‐cell lymphoma 2

HF

heart failure

IR

ischemia/reperfusion

KCa

calcium‐activated potassium channel

LAD

left anterior descending artery

PGC‐1α

PPAR gamma coactivator 1‐alpha

SIRT1

sirtuin 1

Tables of Links

TARGETS
Other protein targets a Enzymes e
FABP4 Acetyl CoA carboxylase
TNF‐α Adenylate cyclase
GPCRs b Akt (PKB)
GLP‐1 receptor ERK1
Nuclear hormone receptors c ERK2
PPARγ FASN
Transporters d Hormone sensitive lipase (HSL)
GLUT4 PDE5A
PKA
SIRT1
LIGANDS
Adiponectin IL‐6
Avanafil Indomethacin
cAMP Insulin
cGMP Liraglutide
Dexamethasone Metformin
Exenatide (exendin‐4) Sildenafil
Exendin (9‐39) Tadalafil
GLP‐1 Vardenafil
IBMX
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,b,c,d,eAlexander et al., 2015a,b,c,d,e).

PDE5

PDEs are a superfamily of enzymes that catalyse the breakdown of the intracellular second messengers cAMP and cGMP into their corresponding inactive 5′‐AMP and 5′‐GMP forms (Bender and Beavo, 2006). In total, 11 PDE families (PDE1–PDE11) (Omori and Kotera, 2007) have been identified, differing in amino acid sequence, affinity and turnover rates for cAMP and cGMP, cellular expression and intracellular localization. Of all the PDEs, PDE5, the main cGMP‐metabolizing enzyme, has been extensively investigated. The three major PDE5 isoforms described and identified are A1, A2 and A3 (Lin et al., 2000a). They share similar cGMP‐catalytic activities but differ at their N‐terminal regions (Lin et al., 2000b). They also showed similar sensitivity to inhibition by sildenafil, although the PDE5A1 isoform seems more resistant than PDE5A2 or PDE5A3 (Lin, 2004). There are no obvious functional differences in PDE5A1, PDE5A2 and PDE5A3. PDE5 was originally identified and purified from rat platelets (Coquil et al., 1980) and lungs (Francis et al., 1980). Although less widely distributed compared with many other PDEs, PDE5 is highly expressed in vascular and bronchial smooth muscle, in renal tubules and in platelets. Its expression in cardiac tissue has been more controversial. Previous studies, aimed at quantifying mRNA (using either RT‐PCR or northern blot) and proteins (using immunohistochemical staining), have demonstrated the expression of PDE5 in heart tissue (Loughney et al., 1998; Wallis et al., 1999), whereas no PDE5 enzymatic activity and/or no immunoreactive bands were observed in human ventricular tissue (Wallis et al., 1999). However, this concept was challenged by a study demonstrating an abundant expression of PDE5 in isolated canine ventricular cardiomyocytes, as assessed by immunohistochemistry (Senzaki et al., 2001), and also in murine ventricular cardiomyocytes, as shown by RT‐PCR, western blot and immunohistochemical assay (Das et al., 2005). PDE5A is generally considered to be a cytosolic protein (Lin, 2004). The sub‐cellular localization of PDE5A, myocyte z‐bands, was not observed when cells were isolated from failing myocytes, suggesting its intracellular localization is altered in these cells (Senzaki et al., 2001). Nevertheless, PDE5 is highly expressed in both experimental and human heart disease (Nagendran et al., 2007; Pokreisz et al., 2009), making it a promising therapeutic target for cardiovascular disease.

PDE5 inhibitors available for patient use

There are currently four commercially available oral PDE5 inhibitors: sildenafil (commonly known as Viagra; Pfizer Inc, Berlin, Germany), vardenafil (Levitra; Bayer HealthCare Pharmaceuticals, Berlin, Germany), tadalafil (Cialis; Eli Lilly, Bad Homburg vor der Höhe, Germany) and avanafil (Stendra; Vivus, Campbell, CA, USA). They all display similar pharmacological properties and structure (Figure 1). Sildenafil, discovered in 1989, was originally developed for the treatment of coronary artery disease (Chrysant and Chrysant, 2012). Although sildenafil did not prove effective for the treatment of coronary heart disease, due to the risk of coronary steal or hypotension, it revealed the interesting side effect of penile erection. These drugs are already in clinical use for the treatment of erectile dysfunction (Boolell et al., 1996). In addition to this, sildenafil (under the trade name Revatio®) (Croom and Curran, 2008) and tadalafil (Adcirca®) (Henrie et al., 2015) were approved by the Food and Drug Administration as vasodilators for the treatment of pulmonary arterial hypertension.

Figure 1.

Figure 1

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Molecular structures of the four clinically approved PDE5 inhibitors: sildenafil, vardenafil, tadalafil and avanafil.

Mechanism of action of PDE5 inhibition

All of the aforementioned, specific PDE5 inhibitors share the same mechanisms of action involving an inhibition of the PDE5 isoenzyme, which prevents cGMP breakdown, thereby increasing its intracellular concentration. Increased cGMP, in turn, activates PKG, stimulates the phosphorylation of proteins regulating smooth muscle tone and reduces cytosolic calcium concentrations. Local regulation of vascular tone and blood flow is primarily dependent upon the release of endothelial NOS‐derived NO. After diffusing from the endothelial cell into subjacent vascular smooth muscle cells, NO activates guanylate cyclase, the enzyme that catalyses the production of cGMP from GTP. As cGMP is degraded by PDE5, inhibiting this enzyme prevents cGMP breakdown, leading to smooth muscle relaxation and consequently vasodilatation. In the myocardium, the cardioprotective mechanisms of PDE5 inhibition include the activation of cGMP‐dependent PKG, which involves the activation of ERK and inhibition of glycogen synthase kinase 3β (GSK3β; Das et al., 2008), and additionally includes the activation of PKC and the opening of mitochondrial ATP‐sensitive potassium channels (KATP channels) (Kukreja et al., 2005), leading to cytoprotection.

Myocardial protection with PDE5 inhibitors

Cardiac PDE5 expression was reported to be up‐regulated in hypertrophic, dilated and ischaemic cardiomyopathy (Nagendran et al., 2007; Pokreisz et al., 2009; Vandeput et al., 2009) and in conditions such as congestive heart failure (HF) (Lu et al., 2010). Therefore, in certain disorders, the pharmacological inhibition of PDE5 could significantly increase intracellular cGMP levels in the myocardium. This restoration of the cardioprotective cGMP–PKG pathway could then exert cardioprotective properties (Kukreja et al., 2012). Therefore, enhanced cGMP signalling by PDE5 inhibition may attenuate myocardial ischaemia/reperfusion (IR) injury. Moreover, recent preclinical studies suggest PDE5 inhibition has direct myocardial effects, which may contribute to its therapeutic effects during heart transplantation and in HF.

Myocardial ischaemia/reperfusion injury

Percutaneous coronary interventions, stenting, coronary bypass surgery, heart transplantation and acute myocardial infarction are associated with myocardial IR injury. Ischaemia is a condition suffered by tissues/organs due to deprived blood flow, followed by an inadequate oxygen and nutrient supply. Paradoxically, the reperfusion of previously ischaemic myocardium acutely causes additional tissue damage. The underlying mechanisms of IR injury are complex and multifactorial. They include intracellular calcium overload or redistribution, the production of ROS, energy depletion, rapid restoration of physiological pH levels and inflammation‐inducing organ dysfunction (Hearse and Bolli, 1992). In the clinical situation, there are four basic types of reperfusion injury: (i) myocardial stunning (Ambrosio and Tritto, 2001), which can be found after reperfusion of a globally ischaemic myocardium or in the setting of regional IR; (ii) reperfusion arrhythmias (Goldberg et al., 1983), including ventricular arrhythmias such as ventricular tachycardia and fibrillation; (iii) lethal, irreversible reperfusion injury (Piper et al., 2003); and (iv) vascular injury (endothelial and microvascular dysfunction including the no‐reflow phenomenon) (Kloner, 1993).

Regional myocardial ischaemia/reperfusion injury

Experimental in vivo studies

There continues to be a great interest in exploring sildenafil's role in myocardial protection against IR injury in animal models. In 2002, it was demonstrated that a treatment of rabbits with sildenafil (0.7 mg·kg−1, iv), 30 min and 24 h prior to ischaemia (30 min) and 3 h of reperfusion, was potent at protecting the myocardium from injury in both the acute and delayed phase, inducing a significant reduction in infarct size compared with the vehicle treatment (Ockaili et al., 2002). This cardioprotective effect is mediated through the opening of mitochondrial KATP channels (Ockaili et al., 2002) and the activation of calcium‐activated potassium (KCa) channels (Wang et al., 2008). This preconditioning‐like effect in the heart has also been observed in other species such as rats (Das et al., 2002), mice (Salloum et al., 2003) and dogs (Reffelmann and Kloner, 2003). Moreover, post conditioning, that is, administration of sildenafil or vardenafil at reperfusion, also induced significant cardioprotection, similar to the preconditioning‐like effects (Salloum et al., 2007). Furthermore, a previous study by Nagy et al. (2004) showed, in dogs, that orally administered sildenafil decreases the incidence of severe life‐threatening ventricular arrhythmias, which arise early after coronary artery occlusion.

Clinical studies

Compared to the extensive in vivo experimental studies, there is a lack of clinical trials examining the protective effects of PDE5 inhibitors against regional IR injury in the myocardium. In a population‐based study, Anderson et al. (2016) showed that in type 2 diabetic patients with a history of acute myocardial infarction or who have suffered acute myocardial infarction during the study period, the use of PDE5 inhibitors (sildenafil, vardenafil or tadalafil) was associated with a lower frequency of acute myocardial infarction and lower mortality.

Global myocardial ischaemia/reperfusion injury

Experimental in vivo studies

Although most in vivo preclinical studies investigating the effects of PDE5 inhibitors were performed in experimental models of myocardial IR, a limited number of studies have been conducted in an in vivo model of global IR injury. In our laboratory, the effects of vardenafil on global IR injury were investigated using our well‐established rat model of heterotopic heart transplantation (Szabo et al., 2002; Loganathan et al., 2015; Hegedus et al., 2016). Our results show that a preconditioning of donor rats with vardenafil (10 μg·kg−1, i.v.), 1 h before explantation, restores systolic and diastolic left ventricular function close to the level of hearts not subjected to IR injury after transplantation (Loganathan et al., 2008). Also, in a clinically relevant large animal model of cardiopulmonary bypass with hypothermic cardiac arrest, we have showed that the application of vardenafil improves myocardial and endothelial functions (Szabo et al., 2009).

Clinical studies

In contrast to preclinical studies, there have been no clinical investigations on the direct effects of PDE5 inhibitors on graft function after transplantation. The clinical studies with PDE5 inhibitors that have been done include patients with pulmonary artery hypertension and/or right ventricular functional recovery after heart transplantation or hypertension. Data from a cohort of high‐risk heart transplant recipients showed that sildenafil has a therapeutic role in the management of acute right ventricular dysfunction in heart transplant recipients with pulmonary hypertension, and can reduce the requirement for inotropes (De Santo et al., 2008). An interesting study published in 2003 (Schofield et al., 2003) demonstrated that 50 mg of sildenafil is well tolerated in hypertensive heart transplant recipients and does not induce hypotension despite the continuation of background antihypertensive medication.

PDE inhibitors in treating heart failure

HF is a condition in which the cardiac contractile performance is insufficient to provide the oxygen requirements of the body, which results in the hypoperfusion of peripheral organs, even at rest. The two main types of HF are acute HF, which develops suddenly, initially with symptoms that are severe, and chronic HF, a long‐term condition that is associated with the heart undergoing adaptive responses (e.g. hypertrophy). Hence, the treatment of HF is a challenging task.

Acute heart failure

Acute decompensated HF is commonly due to left ventricular systolic or diastolic dysfunction, with or without additional cardiac pathologies, such as coronary artery disease or valve abnormalities. The main principles in the treatment of acute HF remain the restoration of oxygenation and the improvement of haemodynamics and organ perfusion. Even though few studies have evaluated the effects of PDE5 inhibitors on acute HF, a previous study by Salloum showed that tadalafil prevents acute HF with reduced ejection fraction in mice (Salloum et al., 2014). However, the potential adverse effects of sildenafil, vardenafil and tadalafil include hypotension (Kloner, 2004), which can be a concern in certain populations of at risk patients. Therefore, these drugs could contribute to adverse clinical outcomes in a number of patients with acute decompensated HF.

Chronic heart failure

Experimental in vivo studies

Volume overload‐induced heart failure

A recent study was the first to show that chronic PDE5 inhibition with sildenafil can attenuate left ventricular remodelling and HF following left ventricular volume overload caused by mechanically‐induced chronic mitral regurgitation (Kim et al., 2012). In this study the cardioprotective effects of sildenafil were associated with its anti‐apoptotic and anti‐inflammatory effects. Sildenafil has been shown to increase both endothelial and inducible NOS proteins, and NO is thought to induce a preconditioning effect in the cardiomyocytes (Das et al., 2005). The preliminary results of Das et al. (2005) suggest that the elevatation of cGMP induced by sildenafil may activate PKG, which contributes to its anti‐apoptotic effects in mouse isolated cardiomyocytes. Additionally, sildenafil treatment has been shown to increase the Bcl‐2 to Bax ratio and, as it is well known that Bcl‐2 is a key anti‐apoptotic protein, this may be one of the factors responsible for the attenuated cardiomyocyte apoptosis (Reed, 1994; Das et al., 2005). Furthermore, sildenafil has been found to reduce the expression of IL‐6, IL‐18, inducible NOS and cyclin‐dependent kinase inhibitor 2a, which further substantiates that it has an inhibitory effect on cardiac inflammation (Kim et al., 2012).

Pressure overload‐induced heart failure

Sustained pressure overload induces pathological cardiac hypertrophy and HF. In a chronic pressure overload mouse model of transverse aortic constriction, Takimoto et al. (2005) showed that blocking the intrinsic catabolism of cGMP by the administration of sildenafil, p.o., suppresses chamber and myocyte hypertrophy and improves in vivo heart function. Furthermore, sildenafil reversed the pre‐established hypertrophy induced by pressure overload, and restored the chamber function to normal (Takimoto et al., 2005).

Congestive heart failure in diabetes mellitus

We have shown that a chronic treatment with vardenafil improves contractile function, without affecting the mean arterial pressure, in a rat model of streptozotocin‐induced diabetic cardiomyopathy (Radovits et al., 2009). Furthermore, vardenafil did not induce a direct positive inotropic effect (no modulating effect on myocardial contractility was observed) in non‐diabetic control rats. Accordingly, the improved cardiac function in the diabetic treated group is a specific phenomenon; this direct cardiac effect of vardenafil reflects a reversal of diabetic cardiomyopathy rather than the consequence of non‐specific effects (Radovits et al., 2009). Recently, Matyas et al. (2017) showed that the treatment of type 2 diabetic rats with vardenafil prevented the development of HF with preserved ejection fraction.

NO production has been shown to activate sirtuin (SIRT)1, a histone deacetylase that binds and activates the PPARγ coactivator (PGC)‐1α, a major regulator of cellular energy metabolism. Chronic treatment with tadalafil has been demonstrated to improve mitochondrial respiratory function via activation of NO‐induced SIRT1‐PGC‐1α signalling (Koka et al., 2014), which attenuates oxidative stress and improves mitochondrial integrity (Koka et al., 2013). Moreover, tadalafil therapy reduces circulating levels of two key pro‐inflammatory cytokines, TNF‐α and IL‐1β, while also improving fasting glucose levels and reducing infarct size following IR injury in obese, diabetic mice (Varma et al., 2012). Additionally, in a model of diabetic cardiomyopathy, chronic sildenafil treatment improves cardiac kinetics and circulating markers through an anti‐remodelling mechanism that is independent of vascular, endothelial or metabolic factors (Giannetta et al., 2012).

Doxorubicin‐induced heart failure

Doxorubicin is associated with both morphological and functional cardiac changes, which are similar to those of dilated cardiomyopathy. In vivo pretreatment of mice with sildenafil has been shown to attenuate doxorubicin‐induced cardiotoxicity (Fisher et al., 2005). Additionally, Koka et al. (2010) also concluded that tadalafil, a long‐acting PDE5 inhibitor, improves left ventricular function and prevents cardiomyocyte apoptosis during doxorubicin‐induced cardiomyopathy in mice. They suggested that the mechanisms of tadalafil involved the up‐regulation of cGMP/PKG activity and manganese superoxide dismutase levels, and that these effects of tadalafil did not interfer with the chemotherapeutic benefits of doxorubicin.

Postinfraction heart failure

Congestive HF, secondary to acute myocardial infarction, continues to be a major complication. Chronic treatment with sildenafil has been shown to attenuate ischaemic cardiomyopathy in mice by limiting necrosis within the first 24 h, and by reducing apoptosis and preserving left ventricular function at 7 and 28 days; it improves survival at 28 days after left anterior descending coronary artery (LAD) ligation, possibly through an NO‐dependent pathway (Salloum et al., 2008). Additionally, Salloum et al. (2014) have shown that chronic treatment with tadalafil, starting immediately following myocardial infarction, attenuates the progression of ischaemic HF in mice. They suggested that tadalafil induces this protective effect by reducing necrosis, apoptosis and myocardial fibrosis, thereby blunting adverse left ventricular remodelling.

Clinical studies

In a randomized, double‐blind, placebo‐controlled study, chronic sildenafil treatment was shown to improve exercise capacity and quality of life (Lewis et al., 2007). It acts as a selective pulmonary vasodilator at rest and during exercise in patients with systolic HF and secondary pulmonary hypertension (Lewis et al., 2007). In line with these observations, a meta‐analysis of randomized clinical trials, comparing sildenafil with a placebo, indicates that sildenafil improves the haemodynamic parameters in HF patients with reduced ejection fraction (Zhuang et al., 2014). Additionally, Bocchi et al. (2002) have shown that a single oral administration of sildenafil to patients with HF was associated with an improvement in exercise capacity. Because sildenafil decreases the left ventricular afterload, it acutely improves cardiac performance in patients with chronic HF (Hirata et al., 2005). Also Guazzi et al. (2007) showed that in chronic HF, sildenafil improves ventilation during exercise and improves aerobic efficiency. This effect of sildenafil was found to be significantly associated with an endothelium‐mediated attenuation of muscle over‐signalling during exercise (Guazzi et al., 2007). Additionally, intermediate‐term administration (4 weeks) of sildenafil to outpatients with stable but chronic HF improves exercise performance and ventilatory efficiency, oxygen uptake kinetics and pulmonary hypertension (Behling et al., 2008). However, these beneficial effects were not confirmed by the RELAX trial (Redfield et al., 2013). In this trial, chronic treatment with sildenafil for 24 weeks did not improve exercise capacity, quality of life, clinical status or left ventricular remodelling in 216 elderly HF with preserved ejection fraction patients when compared with a placebo. The lack of beneficial effects of sildenafil in this RELAX trial is not fully understood but may be attributable to the fact that the patients did not have pulmonary hypertension or to the fact that an impaired cGMP ‘production’, rather than an increased ‘degradation’, may be the predominant pathophysiological mechanism in HF with preserved ejection fraction (Redfield et al., 2013). According to novel experimental data, long‐term PDE5 inhibition might serve as a useful tool to prevent the development of HF with preserved ejection fraction in high risk patients (such as diabetics), rather than to treat/reverse the symptoms of this disease (Matyas et al., 2017).

Potential mechanisms

The potential mechanisms by which PDE5 inhibition improves myocardial function are complex and are summarized in Figure 2. The prominent expression of PDE in bronchial smooth muscle and in blood vessels suggests that PDE5 inhibitors exert their beneficial cardiac effects by affecting systemic and regional haemodynamics. However, experimental studies suggest sildenafil has a direct protective effect on adult cardiomyocytes against necrosis and apoptosis following ischaemia/reoxygenation injury. The underlying mechanism involves the NO signalling pathway (Das et al., 2005). In addition, Guazzi (2008) has shown that the increase in cGMP activity evoked by inhibition of PDE5 has a direct effect on the myocardium, independent of the vascular action that may block adrenergic, hypertrophic and pro‐apoptotic signalling and contribute to this cardioprotective effect.

Figure 2.

Figure 2

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Proposed mechanisms for the cardioprotective actions of PDE5 inhibitors. PDE5 inhibitors activate PKG by preventing the breakdown of cGMP and increasing the generation of NO‐driven cGMP. The NO–cGMP–PKG signalling pathway has a direct cardioprotective effect on the myocardium by opening mitochondrial ATP‐dependent potassium channels (mitoKATP) and stimulating calcium activated potassium channels (KCa). In addition, PDE5 inhibition promotes anti‐apoptotic and anti‐inflammatory effects, decreases hypertrophy, ventricular arrhythmias and myocardial fibrosis and also reduces oxidative stress by activating SIRT1. The NO–cGMP–PKG pathway also leads to beneficial cardiac effects by inducing direct vasodilator responses. Hence, basic science data and clinical studies suggest PDE5 inhibitors have potential as a treatment for myocardial IR injury and chronic HF.

Apart from inhibiting PDE5, PDE5 inhibitors also possess antioxidant activity. It has been shown that oxidative stress increases the expression of PDE5 in the cardiomyocytes of failing hearts (Lu et al., 2010) and sildenafil attenuated oxidative stress by inhibiting free radical formation and by facilitating antioxidant redox systems (Bivalacqua et al., 2009; Perk et al., 2008). One of the mechanisms of action of PDE inhibitors might be to reduce oxidative stress levels, as PDE levels are up‐regulated in conditions such as pulmonary hypertension, chronic HF and right ventricular hypertrophy (Corbin et al., 2005; Forfia et al., 2007; Nagendran et al., 2007) and oxidative stress mediates the dysfunctional NO–cGMP–PKG signalling in cardiovascular disease. Therefore, PDE5 inhibitors may have therapeutic benefits in a variety of pathologies (Das et al., 2015).

Conclusions

While evidence from experimental data and to a lesser extent clinical studies suggest that PDE5 inhibitors are cardioprotective, carefully conducted clinical trials are required before extrapolating the encouraging results of these experimental studies to clinical indications. The re‐purposing of these drugs represents an attractive option for the treatment of patients with advanced HF and diabetic patients with HF, and also may be suitable for a wide range of other clinical areas, such as heart transplants, coronary bypass surgery, acute myocardial infarction and pathological cardiac hypertrophy.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

The authors thank Dr Mihály Ruppert for his constructive comments and Paige Brlecic for English corrections. This work was supported by the Land Baden‐Württemberg, Germany, by the Medical Faculty of the University of Heidelberg, Germany (to Dr S. Korkmaz‐Icöz), by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (to Dr T. Radovits) and by the National Research, Development and Innovation Office of Hungary (NKFIA; NVKP‐16‐1‐2016‐0017).

Korkmaz‐Icöz, S. , Radovits, T. , and Szabó, G. (2018) Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure. British Journal of Pharmacology, 175: 223–231. doi: 10.1111/bph.13749.

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