Sildenafil citrate in healthy and diseased hearts

Sildenafi l citrate is one of the frontline drugs used to manage erectile dysfunction (ED). Chemically, it is described as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H –pyrazolo [4,3-d] pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6O4 S). It is a highly selective inhibitor of cyclic guanine monophosphate-specifi c phosphodiesterase type-5. There had been heightened concerns following reports that sildenafi l citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. So the cardiac electrophysiological eff ects of sildenafi l citrate have been investigated extensively in both animal and clinical studies. This article ties up the various outcomes of the investigations with a view to guiding physicians and patients that use sildenafi l citrate to manage erectile dysfunction, especially as it concerns its eff ect on their cardiovascular function in health and in disease. Sildenafi l citrate could impact negatively on ailing hearts, but on a healthy heart, there may not be any such impact, rather, it improves on heart performance as it lowers the blood pressure.


Erectile dysfunction
Erectile Dysfunction (ED) is a major health challenge across the world, prevalent among men of between 40 and 70 years, and indeed above 70 years. It is de ined as the inability to achieve and/or maintain an erection suf icient for satisfactory sexual activity [1,2]. Incidentally, many men within this age range are predisposed to one cardiovascular disease or the other. It is considered to be a signi icant medical condition because it can lead to a loss of self-esteem, frustration, depression, and dif iculty with disruption of sexual relationships [3].

Sildenafi l citrate
Sildena il citrate is a frontline drug approved for the treatment of erectile dysfunction (ED). It is phosphodiesterase type-5 (PDE5) inhibitor, relaxing blood vessels in the penis thereby facilitating erection. The inhibitor actually blocks the enzyme PDE5, which prevents relaxation of smooth muscle tissue.
There have been several claims of death associated with use of sildena il citrate, especially among patients with history of cardiovascular diseases. This has therefore raised some concerns regarding its safety in patients with coronary artery disease [4].

Heart and heart diseases
The heart is a muscular pump that provides the force necessary to circulate the blood to all the tissues in the body. Its function is vital because, to survive, the tissues need a continuous supply of oxygen and nutrients, and metabolic waste products have to be removed. Deprived of these necessities, cells soon undergo irreversible changes that lead to death. While blood is the transport medium, the heart is the organ that keeps the blood moving through the vessels. The normal adult heart pumps about 5 liters of blood every minute throughout life. If it loses its pumping ability for even a few minutes, the individual's life is jeopardized (Figure 1).

Heart disease
Heart disease refers to various types of conditions that can affect heart function. These types include: Coronary artery (atherosclerotic) heart disease that affects the arteries to the heart; Valvular heart disease that affects how the valves function to regulate blood low in and out of the heart. Cardiomyopathy that affects how the heart muscle squeezes; Heart rhythm disturbances (arrhythmias) that affect the electrical conduction; Heart infections where the heart has structural problems that develop before birth; Coronary artery disease is the most common type of heart disease.
Coronary arteries supply blood to the heart muscle and coronary artery disease occurs when there is a buildup of cholesterol plaque inside the artery walls. Over time, this buildup of plaque may partially block the artery and decrease blood low through it.
A heart attack occurs when a plaque ruptures and forms a clot in the artery causing a complete blockage. That part of the heart muscle that is denied blood supply starts to die.
Classic signs and symptoms of coronary heart disease may include: chest pain (angina) -this pain may radiate or move to the arm, neck, or back, shortness of breath, sweating, nausea, irregular heartbeat Not all people with coronary artery disease have chest pain as a symptom. Some may have signs and symptoms of indigestion or exercise intolerance where they cannot perform activities that they normally once could.
Coronary heart disease is initially diagnosed by patient history and physical examination. EKG blood tests and tests to image the arteries and heart muscle con irm the diagnosis.
Treatment for coronary heart disease depends upon its severity. Many times lifestyle changes such as eating a heart-healthy diet, exercising regularly, stopping smoking, and controlling high blood pressure, high cholesterol, and diabetes may limit the artery narrowing. In some people, surgery or other procedures might be needed.

Erectile dysfunction and cardiovascular disease
ED is a common health concern among patients with cardiovascular disease. According to a research report, 34.8% of men aged 40 to 70 years have moderate to complete ED, and 15% of men aged 70 have complete ED [3].
The risk of ED has been shown to increase with age, with a high prevalence of ED found in patients with cardiovascular disease [3]. A research report has shown a signi icant correlation between the severity of ED and the number of vessels involved in patients with coronary artery disease (CAD) [5].
The age-adjusted prevalence of complete ED has been reported to be 1.5 times higher in men with hypertension than in the entire population studied [3]. Epidemiologic studies have shown that ED shares important risk factors with coronary artery disease; they are both prevalent among smokers, diabetics and patients with hypercholesterolemia [6]. Another report also found that patients with CAD and peripheral vascular disease have an increased prevalence of ED [7].

Sildenafi l citrate and erectile dysfunction
Seeing the frustration and consequent depression associated with erectile dysfunction, increasing attention has recently been given to it, especially with the advent of effective oral treatments [8]. Although ED was once diagnosed and treated primarily by urologists, primary healthcare physicians and other specialists such as cardiologists now write about 80% of the prescriptions for sildena il citrate, the most popular drug used to treat this condition [9].
Sildena il citrate is a frontline choice for the treatment of ED because it selectively inhibits phosphodiesterase type 5 (PDE-5) [10], which inactivates cyclic guanine monophosphate (cGMP), the mediator of smooth muscle relaxations in the corpus cavernosum. By selectively inhibiting cGMP catabolism in cavernosal smooth-muscle cells [10], sildena il citrate can restore the natural erectile response to sexual stimulation without causing erections in the absence of such stimulation. It is rapidly absorbed, with maximal plasma concentrations occurring within an hour after oral administration and a mean terminal half-life of 3 to 5 hours [10]. So, sildena il citrate has been shown to be an effective treatment for ED.
However, the report of several deaths reported in patients taking the drug in the 90s raised the question as to whether the death was caused by the drug or triggered by an underlying disease such as ischemia, and not linked to a speci ic drug effect [11]. Nevertheless, the death reports raised concerns that sildena il citrate may increase the risk of cardiovascular events in men with ED and cardiovascular disease [12], which led to many basic and clinical investigations of the adverse cardiovascular effects of the drug [12].

Mechanism of action of Sildenafi l citrate
Sildena il protects cyclic guanosine monophosphate (cGMP) from degradation by cGMP-speci ic phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased in low of blood into the spongy tissue of the penis, causing an erection [13].
The molecular mechanism of smooth muscle relaxation involves the enzyme CGMP-dependent protein kinase, also known as PKG. This kinase is activated by cGMP and it phosphorylates multiple targets in the smooth muscle cells, namely myosin light chain phosphatase, RhoA, IP3 receptor, phospholipase C, and others [14]. Overall, this results in a decrease in intracellular calcium and desensitizing proteins to the effects of calcium, engendering smooth muscle relaxation [14].
Sildena il is a potent and selective inhibitor of cGMP-speci ic phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildena il is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and increased penile response to sexual stimulation [13,14]. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildena il should not cause an erection.

Mechanism of metabolic sildenafi l citrate
Sildena il is broken down in the liver by hepatic metabolism using cytochrome p450 enzymes, mainly CYP450 3A4 (major route), but also by CYP2C9 (minor route) hepatic isoenzymes. The major product of metabolisation by these enzymes is N-desmethylated sildena il, which is metabolized further. This metabolite also has an af inity for the PDE receptors, about 40% of that of sildena il. Thus, the metabolite is responsible for about 20% of sildena il's action. Sildena il is excreted as metabolites predominantly in the feces (about 80% of administered oral dose) and to a lesser extent in the urine (around 13% of the administered oral dose). If taken with a high-fat meal, absorption is reduced; the time taken to reach the maximum plasma concentration increases by around one hour, and the maximum concentration itself is decreased by nearly one-third [15].

Use of sildenafi l citrate in patients with cardiovascular disease
Sildena il citrate is a cGMP-speci ic PDE-5 inhibitor [10]. PDE-5, which is located primarily in the cavernous body, thrombocytes and vascular smooth muscle cells, degrades cGMP [16]. Thus, by inhibiting PDE-5, sildena il citrate selectively increases cGMP levels [10]. It shows far less af inity for other phosphodiesterase isozymes, including PDE-1, which is abundant in ventricular myocytes [17]. However, concern about adverse cardiovascular effects remains [18] since PDE-5 inhibitors promote vasodilation, and thus has the potential to cause hypotension. This concern has been greatest for elderly patients with pre-existing cardiovascular disease. A review of the clinical database for this drug, which supports its cardiovascular safety in a wide range of patients abounds.
During placebo-controlled trials, the rate of myocardial infarction (MI) or cardiovascular death was 0.91 (95% CI: 0.52-1.48) per 100 person-years (PY) of follow-up among sildena il citrate-treated patients compared with 0.84 (95% CI: 0.39-1.60) per 100 PY of follow-up among placebo-treated patients. The relative risk of MI or cardiovascular death was 1.08 (95% CI: 0.45-2.77) for sildena il citrate compared with placebo (p = 0.88). During open-label studies, the rate of MI or cardiovascular death was 0.56 (95% CI: 0.44-0.72) per 100 PY of follow-up. This analysis shows that rates of MI and cardiovascular death are low and comparable between men treated with sildena il citrate and those treated with placebo, suggesting that the use of sildena il citrate is not associated with an increase in the risk of MI or cardiovascular death [19].
Another study on male patients that were referred for coronary angiography with a diagnosis of chronic stable angina also revealed that sildena il citrate is not associated with adverse cardiovascular effects. Hemodynamic measurements were taken during right and left heart catheterization in the basal state, and 60 min after 50 mg of oral sildena il. A single oral dose of sildena il citrate had no signi icant hemodynamic effects in supine patients with stable angina [20]. This shows that isolated administration of sildena il citrate does not appear to be associated with adverse cardiovascular effects.

Hypotensive risk of Sildenafi l citrate with patients on anti-hypertensive drugs
It has been recommended that patients taking sildena il citrate with combinations of antihypertensive drugs (such as calcium-channel blockers, ß-blockers, diuretics, and angiotensin-converting enzyme inhibitors) be alerted to the possibility of hypotension, particularly patients with congestive heart failure [21]. Therefore, patients with wellcontrolled hypertension can be safely managed with approved medical treatments for ED [12]. However, concomitant use of nitrates is considered to be an absolute contraindication for the use of sildena il citrate to avoid the risk of hypotension [22].

Nitrites
Nitrates are prescribed in several different forms, including sublingual nitroglycerin, oral isosorbide mononitrate or dinitrate, nitropatch, and nitropaste, all of which have been associated with a prolonged decrease in blood pressure when used concomitantly with sildena il citrate [22].
They are metabolized in vessel walls, where they release nitric oxide. Sildena il citrate prolongs the vasodilatory effects of nitrates by decreasing the breakdown of nitric oxide's main effector, cGMP. It is not sure how much time must elapse between administration of sildena il citrate and administration of nitrates to avoid signi icant hypotensive effects [22], but it has been suggested to assume an interval of at least 24 hrs [22]. Nitroprusside also causes vasodilatation by non-enzymatic release of nitric oxide, and thus is predicted to have a synergistic hypotensive effect with sildena il citrate [22].

Eff ects of sildenafi l citrate on cardiac contractility, blood pressure and heart rate
Sildena il citrate belongs to a class of compounds called PDE inhibitors. PDEs comprise a diverse family of enzymes that hydrolyze cyclic nucleotides (cAMP and cGMP) and therefore play a critical role in the modulation of second messenger signaling pathways [16]. Sildena il citrate is an inhibitor that is about 4,000 times highly selective of human PDE-5 over human PDE-3 [22]. This is important because inhibitors of PDE-3 (the isozyme involved in the regulation of cardiac contractility), such as milrinone, vesnarinone and enoximone, which have been used in patients with heart failure, are generally associated with an increased incidence of cardiac arrhythmias and other serious side effects [23]. The cardiotoxic effects of PDE-3 inhibitors are thought to be related to an increase in intracellular cAMP in the myocardium [24,25]. However, PDE-5 is not present in cardiac myocytes [25]. Corbin and colleagues [26] demonstrated in both dog and human hearts that sildena il citrate was unlikely to directly produce an inotropic effect on cardiac muscle.
Systemic and pulmonary arterial and venous smooth muscle cells contain PDE-5. However, sildena il citrate causes only a mild and transient decrease in blood pressure (8-10 mmHg for systolic blood pressure and 5-6 mmHg for diastolic blood pressure) [19]. The peak effects are evident 1 h after the dose is given and last for approximately 4 h [19]. Heart rate and cardiac output are not signi icantly affected. Along with a mild decrease in systemic vascular resistance and afterload, there is also a mild decrease in preload and stroke volume due to venous vasodilatation. These effects are not dependent upon age or dose (within the range of 25 to 800 mg) [25]. In a study of patients with severe coronary artery disease, it has been con irmed that the hemodynamic effects of sildena il citrate (when taken alone) are not associated with clinically signi icant hypotension [27}.

Eff ects of sildenafi l citrate on central hemodynamics and peripheral vasculature
In normal volunteers, no signi icant changes in cardiac index were evident up to 12 h after administration of oral sildena il citrate (100 to 200 mg) or intravenous sildena il citrate (20 to 80 mg) [25]. Signi icant decreases in the systemic vascular resistance index were reported at the end of intravenous sildena il citrate infusion (20 to 80 mg), when plasma concentrations were highest [25]. Sildena il citrate has both vasodilator and venodilator effects on the peripheral vasculature [25]. In 8 patients with stable angina, intravenous sildena il citrate reduced systemic and pulmonary arterial pressures, as well as cardiac output, by 8, 25, and 7%, respectively, consistent with its mixed arterial (systemic and pulmonary hypotension) and venous (drop in stroke volume secondary to decreased preload) vasodilator effects [28].
Although the therapeutic ef icacy of sildena il citrate in the treatment of ED has been proven, little is known about the potential bene icial effects of sildena il citrate in other diseases. Studies in rats demonstrated that PDE-5 inhibition with sildena il attenuates the rise in pulmonary artery pressure and vascular remodeling when given before chronic exposure to hypoxia-induced pulmonary hypertension [29]. Likewise, clinical investigations in patients with pulmonary arterial hypertension have shown that sildena il citrate therapy may be bene icial to patients receiving long-term infusion of epoprostenol [30,31]. A recent meta-analysis study has suggested that the validity of the observed effect of sildena il on pulmonary hypertension is not conclusive due to small participant numbers and inadequate investigation of different disease etiologies. In addition, further studies are needed to investigate the long-term outcome [32].

Cardiac electrophysiological eff ects of sildenafi l citrate
In the past few years, the cardiac electrophysiological effects of sildena il citrate have been investigated extensively [33]. Geelen and colleagues [33] demonstrated that sildena il citrate induces a dose-dependent block of the rapid component of the delayed recti ier potassium current (I Kr ). They also reported that sildena il citrate can have an action similar to that of class III antiarrhythmic drugs [33]. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insuf iciency, during co-administration of another CYP3A4 inhibitor, or after drug overdose [11]. Prolonged cardiac repolarization caused by sildena il citrate could result in malignant ventricular arrhythmias and lead to sudden cardiac death in some of these patients [11]. Swissa and colleagues [34] demonstrated that a combination of sildena il citrate and a nitric oxide donor increases ventricular tachyarrhythmia/ VF vulnerability in the normal right ventricle of swine.
Although many reports have demonstrated the arrhythmogenic effects of sildena il citrate, some studies have reported otherwise. Vardi and colleagues [35] showed that sildena il citrate does not alter the hemodynamic responses to exercise or change the incidence of ventricular arrhythmias in men with cardiovascular disease and ED. Chiang and colleagues [36] found that sildena il citrate at concentrations up to 30 μM has no signi icant effect on either the rapid (I Kr ) or the slow (I Ks ) components of the delayed recti ier potassium currents in guinea pig ventricular myocytes. They also found that sildena il citrate dose-dependently blocks L-type Ca 2+ currents (I Ca,L ), but has no effect on persistent Na + currents. They concluded that sildena il citrate does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably via its blocking effect on I Ca,L [36]. Recent studies have also demonstrated that oral administration of 50 mg sildena il citrate does not affect QT dynamic properties [37]. Furthermore, Nagy and colleagues [38] recently reported that sildena il citrate reduces arrhythmia severity during ischemia 24 h after oral administration in dogs.

Cardioprotective eff ects of sildenafi l citrate
Ischemic preconditioning often results in powerful cardioprotective effects [39]. Repeated brief episodes of ischemia initiate a cascade of intracellular signaling events which help prevent future myocardial infraction and stunning [39]. After initial observation, this phenomenon, termed "myocardial preconditioning, was studied intensively to try to understand its cellular mechanisms and apply this knowledge towards protection of the human heart from ischemic heart disease. Current data suggest that sildena il citrate has a preconditioning-like cardioprotective effect in the rabbit, rat and mouse heart [40]. Das and colleagues [41] reported that sildena il citrate at a much lower dose (0.05 mg/kg) provides signi icant cardioprotection in isolated perfused rat hearts following global ischemic-reperfusion. They observed an improved post-ischemic recovery of ventricular function, a reduction in the incidence of VF, and a decrease in MI. At higher doses, sildena il caused a signi icant increase in the incidence of VF, while at very low doses it had no effect on cardiac function [41]. However, a study by Reffelmann and Kloner [42] demonstrated otherwise. In their report, they did not ind a decrease in myocardial necrosis following ischemia-reperfusion in a rabbit model. The reason for these negative results was not clear. The only noticeable difference in the experimental procedure was a considerably longer drug infusion time (~5 min) in the study by Reffelmann and Kloner [42] as compared to that used by Ockaili and colleagues [42] (~1 min), which could potentially affect the hemodynamic response prior to ischemia.

Signaling mechanisms in sildenafi l-induced cardioprotection
Although sildena il citrate has been shown to have a powerful preconditioning-like cardioprotective effects in animal models of ischemia-reperfusion injury, the precise cellular mechanism underlying these effects remains yet unclear. The sildena il citrate-induced cardioprotective effect against ischemia-reperfusion injury is dependent upon the opening of mitochondrial ATP-sensitive potassium channels (mitoK ATP channels) in rabbits [43]. It has been proposed that the vasodilatory action of sildena il citrate could potentially cause the release of endogenous mediators of preconditioning, such as adenosine or bradykinin from endothelial cells, which may trigger a signaling cascade (through the action of kinases) and the release of nitric oxide [43]. Generation of nitric oxide could potentially activate guanylate cyclase, resulting in an enhanced formation of cGMP [44]. cGMP may activate protein kinase G, which could then open mitoK ATP channels, resulting in both acute and delayed cardioprotective effects [45]. Mitochondria are known to play an essential role in cell survival via ATP synthesis and maintenance of Ca 2+ homeostasis [46]. Opening mitoK ATP channels partially compensates the membrane potential, which enables additional protons to be pumped out to form an H + electrochemical gradient to drive both ATP synthesis and Ca 2+ transport. Recently, it was reported that protein kinase C also plays an essential role in sildena il-induced cardioprotection in rabbits [47].

Conclusion
Going by the extensive data available to date, sildena il citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions, however, are needed for patients with cardiovascular disease, particularly as it concerns patients treating CVD with nitrites. This is because PDE-5 inhibitors promote vasodilation, and thus has the potential to cause hypotension. This concern has been greatest for elderly patients with pre-existing cardiovascular disease. Therefore doctors managing ED with sildena il citrate must irst be sure that the patient does not have a CVD or managing any cardiovascular disease with nitrites.
It is also evident that sildena il may have some cardioprotective effect on healthy hearts via some complex cell signaling pathway. Vasodilatory action of sildena il citrate could potentially cause the release of endogenous mediators of preconditioning, such as adenosine or bradykinin from endothelial cells, which may trigger a signaling cascade (through the action of kinases) and the release of nitric oxide. The nitric oxide so released could potentially activate guanylate cyclase, resulting in an enhanced formation of cGMP. The cGMP may activate protein kinase G, which could then open mitoK ATP channels, resulting in both acute and delayed cardioprotective effects. Further clinical and basic investigation on the cardiovascular effects of sildena il citrate in this regard will help the world of knowledge.