Sildenafil in Erectile Dysfunction and Cardiovascular Medicine: From Nitric Oxide–cGMP Signaling to Myocardial Protection, Hemodynamic Regulation, Clinical Safety, and Emerging Therapeutic Opportunities—A State-of-the-Art Review

Figure 1: NO–cGMP–PDE5 signaling pathway and mechanism of sildenafil

2.5 Pharmacokinetics

Sildenafil is rapidly absorbed following oral administration. Current prescribing information indicates a mean absolute bioavailability of approximately 41%, with maximum plasma concentrations generally occurring within approximately 30–120 minutes under fasting conditions. Pharmacokinetics are approximately dose proportional across the recommended therapeutic range. Administration with a high-fat meal can delay absorption and reduce the peak plasma concentration, although the overall exposure is less substantially affected (U.S. Food and Drug Administration [FDA], 2025).

Sildenafil undergoes extensive hepatic metabolism, predominantly through cytochrome P450 3A4 (CYP3A4), with CYP2C9 contributing as a secondary metabolic pathway. The major circulating metabolite is N-desmethyl sildenafil, which retains pharmacological activity but has lower PDE5 inhibitory potency than the parent compound. Both sildenafil and its active metabolite have terminal half-lives of approximately 4 hours, supporting the relatively limited duration of systemic exposure compared with longer-acting PDE5 inhibitors (FDA, 2025).

Age and organ function can influence sildenafil exposure. Older individuals may demonstrate increased plasma concentrations because of age-related alterations in hepatic metabolism and drug clearance. Similarly, hepatic impairment can increase systemic exposure, while severe renal impairment may reduce clearance and increase circulating drug concentrations. CYP3A4 inhibitors can also substantially increase sildenafil exposure, making dose adjustment clinically relevant in susceptible patients (FDA, 2025). These pharmacokinetic characteristics provide an important basis for individualized dosing and assessment of potential drug–drug interactions.

2.6 Pharmacodynamic Considerations

The pharmacodynamic response to sildenafil is closely related to PDE5 inhibition and the availability of endogenous NO. Following administration, increased cGMP availability facilitates cavernosal smooth-muscle relaxation when sexual stimulation activates nitrergic and endothelial pathways. Sildenafil therefore enhances physiological erectile responses rather than producing an erection through direct central or peripheral stimulation. Clinical effects generally begin within a relatively short period after oral administration, with pharmacological activity extending for several hours, although the duration of clinically useful erectile responsiveness varies between individuals.

The relationship between dose and response is not completely linear from a clinical perspective. Increasing the dose can increase drug exposure and pharmacological effects but may also increase the probability of dose-related adverse effects, including headache, flushing, dyspepsia, nasal congestion, dizziness, and visual disturbances. Consequently, therapeutic optimization requires balancing erectile efficacy with tolerability rather than simply maximizing PDE5 inhibition.

An important pharmacodynamic feature of sildenafil is its dependence on sexual stimulation. In the absence of NO release and subsequent cGMP synthesis, PDE5 inhibition alone cannot generate the complete biochemical sequence required for erection. Sildenafil therefore functions primarily as an amplifier of physiological NO–cGMP signaling. This mechanism provides the fundamental explanation for its selective therapeutic action in ED and also establishes the pharmacological basis for investigating PDE5 inhibition in other disorders characterized by impaired vascular or cGMP signaling (Samidurai et al., 2023; Pușcașu et al., 2023).

Table 1. Pharmacokinetic and Pharmacodynamic Properties of Sildenafil

3. Sildenafil in Erectile Dysfunction: Efficacy, Mechanisms, and Clinical Applications

3.1 Pathophysiology of Erectile Dysfunction

Erectile dysfunction (ED) is a multifactorial disorder characterized by the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual activity. Its pathogenesis involves vascular, neurological, endocrine, metabolic, psychological, and medication-related factors, which frequently coexist within the same patient (MacDonald & Burnett, 2021). Consequently, ED is increasingly regarded as a systemic disorder rather than an isolated penile condition.

Vasculogenic ED represents one of the most important organic forms and is associated with impaired arterial inflow, endothelial dysfunction, atherosclerosis, and abnormalities of cavernosal smooth-muscle relaxation. Because penile arteries are relatively small, vascular impairment may become clinically apparent in the penis before symptoms of cardiovascular disease develop. Endothelial dysfunction reduces nitric oxide (NO) availability and consequently compromises the NO–cGMP pathway required for normal erection (Pescariu et al., 2022).

Neurogenic ED results from impairment of the neural pathways responsible for erection. Spinal cord injury, multiple sclerosis, Parkinsonian disorders, peripheral neuropathy, pelvic surgery, and other neurological conditions can interfere with parasympathetic and nitrergic signaling. Neurogenic and vascular mechanisms may coexist, particularly in patients with diabetes or pelvic disease (Minervini et al., 2021).

Diabetes-associated ED is particularly important because chronic hyperglycemia promotes endothelial dysfunction, oxidative stress, vascular injury, autonomic neuropathy, and structural alterations of penile tissue. These abnormalities can reduce the responsiveness of cavernosal tissue to endogenous NO and may contribute to a less robust response to PDE5 inhibitors. Nevertheless, sildenafil remains an effective therapeutic option in many men with diabetes-associated ED (Yuan et al., 2018).

Medication-associated ED may occur with several commonly prescribed drugs, including certain antihypertensive agents, antidepressants, antipsychotics, antiandrogens, and other medications affecting vascular, hormonal, or central nervous system pathways. Identification of potentially contributing medications is therefore an important component of ED assessment.

Psychogenic and mixed ED involve anxiety, depression, relationship difficulties, performance-related stress, and other psychological factors. In clinical practice, purely psychogenic or purely organic ED is less common than mixed disease, because psychological distress may develop secondary to organic erectile difficulties and subsequently worsen erectile performance (MacDonald & Burnett, 2021).

Metabolic abnormalities are also closely associated with ED. A recent systematic review and meta-analysis demonstrated a strong association between metabolic syndrome and ED, with individual components such as obesity, hypertension, dyslipidemia, and abnormal glucose metabolism contributing substantially to erectile impairment (Corona et al., 2023).

3.2 Mechanism of Erectile Action

Normal penile erection begins with sexual stimulation, which activates parasympathetic and nitrergic nerves and promotes NO release from both neuronal and endothelial sources. NO activates soluble guanylate cyclase within cavernosal smooth-muscle cells, resulting in increased intracellular cGMP. The subsequent activation of cGMP-dependent signaling reduces intracellular calcium availability and promotes relaxation of cavernosal smooth muscle.

Sildenafil selectively inhibits PDE5, the principal enzyme responsible for cGMP degradation in the corpus cavernosum. By reducing cGMP breakdown, sildenafil amplifies and prolongs the physiological signal generated following sexual stimulation. The resulting smooth-muscle relaxation produces dilation of penile arteries and arterioles and increases blood flow into the corpora cavernosa (MacDonald & Burnett, 2021).

As cavernosal spaces fill with blood, expansion of the erectile tissue compresses subtunical venules against the surrounding tunica albuginea. This veno-occlusive mechanism decreases venous outflow and allows intracavernosal pressure to rise sufficiently to produce and maintain penile rigidity. Therefore, sildenafil primarily facilitates the physiological mechanisms of erection rather than directly inducing an erection in the absence of sexual stimulation.

The clinical importance of this mechanism is that sildenafil acts as a signal amplifier within an intact NO–cGMP pathway. Men with severe endothelial, neural, or structural impairment may therefore have a reduced response despite appropriate treatment.

3.3 Clinical Efficacy

Sildenafil is an established first-line pharmacological treatment for most men with ED. Contemporary international recommendations continue to place PDE5 inhibitors among the principal medical therapies because of their established efficacy, oral administration, and generally predictable safety profile (European Association of Urology [EAU], 2026; Nehra et al., 2025).

Clinical efficacy is generally assessed using validated instruments such as the International Index of Erectile Function–Erectile Function domain (IIEF-EF), Sexual Encounter Profile (SEP), Global Assessment Questions, and patient-reported treatment satisfaction. Sildenafil has consistently demonstrated improvements in erectile function, ability to achieve penetration, maintenance of erection, and successful intercourse compared with placebo.

Dose optimization is an important component of treatment. Sildenafil is commonly initiated at 50 mg and may be adjusted according to efficacy and tolerability, with lower doses appropriate for selected patients and higher doses considered when the initial response is inadequate and no safety limitation exists. Contemporary guidance emphasizes that inadequate treatment response should not immediately be interpreted as pharmacological failure; incorrect administration, insufficient sexual stimulation, inappropriate timing, inadequate treatment exposure, and failure to titrate the dose can all contribute to apparent nonresponse (EAU, 2026).

Importantly, clinical response may vary according to the underlying cause of ED. Men with diabetes, severe vascular disease, advanced endothelial dysfunction, or significant neurological impairment may exhibit a less pronounced response than men with predominantly mild vasculogenic or psychogenic disease.

3.4 Sildenafil in Special Patient Populations

Diabetes Mellitus

Diabetes is associated with both vascular and neurogenic mechanisms of ED, making treatment more challenging. Nevertheless, sildenafil produces clinically meaningful improvements in erectile function in many diabetic men. Meta-analytic evidence has demonstrated significant improvement in overall sexual performance compared with placebo in men with diabetes-associated ED (Yuan et al., 2018). In addition, observational evidence suggests that ED itself identifies an important cardiovascular-risk phenotype in diabetic populations (Seidu et al., 2022).

Hypertension

Hypertension contributes to ED through endothelial dysfunction, vascular remodeling, impaired NO signaling, and the effects of some antihypertensive medications. Sildenafil can generally be used in appropriately selected hypertensive patients and may improve erectile function without clinically important additional blood-pressure effects in most patients receiving stable antihypertensive therapy. Contemporary European guidance notes that PDE5 inhibitors may produce small additive reductions in blood pressure when combined with antihypertensive medications, which are generally clinically modest.

Obesity and Metabolic Syndrome

Obesity is strongly associated with ED through insulin resistance, inflammation, oxidative stress, endothelial dysfunction, reduced physical activity, and hormonal alterations. A 2023 systematic review and meta-analysis found that metabolic syndrome was associated with a substantially increased risk of ED, while emphasizing that management of individual metabolic abnormalities remains particularly important (Corona et al., 2023). Lifestyle modification, weight reduction, improved metabolic control, and pharmacological treatment can therefore complement sildenafil therapy rather than being viewed as separate interventions.

Older Adults

Age-related changes in endothelial function, vascular compliance, testosterone status, neurological signaling, and comorbidity burden increase the prevalence of ED among older men. Sildenafil remains useful in this population, although treatment should be individualized according to renal and hepatic function, cardiovascular status, concomitant medications, and susceptibility to adverse effects.

Patients With Cardiovascular Disease

ED and cardiovascular disease share major risk factors, including hypertension, diabetes, dyslipidemia, obesity, smoking, and endothelial dysfunction. Consequently, the appearance of ED may provide an opportunity for cardiovascular-risk assessment. Importantly, PDE5 inhibitors should be distinguished from nitrate therapy because concomitant administration with nitrates can produce clinically significant hypotension. In appropriately assessed cardiovascular patients who are not receiving contraindicated nitrate therapy, sildenafil can remain an effective treatment option (Pescariu et al., 2022; EAU, 2026).

Patients With Endothelial Dysfunction

Endothelial dysfunction represents an important mechanistic link between ED and cardiovascular disease. Reduced NO bioavailability limits cGMP generation and can consequently decrease erectile responsiveness. This relationship explains why ED is frequently observed in patients with cardiometabolic disorders and why cardiovascular-risk-factor modification should accompany symptomatic ED treatment.

3.5 Comparison With Other PDE5 Inhibitors

Sildenafil, tadalafil, vardenafil, and avanafil share the same fundamental therapeutic strategy—enhancement of NO-mediated cGMP signaling—but differ in pharmacokinetic characteristics, duration of action, food effects, and adverse-effect profiles.

Sildenafil versus tadalafil: Sildenafil is generally administered approximately 1 hour before sexual activity and has a relatively short plasma half-life of about 3–5 hours. Tadalafil has a substantially longer half-life of approximately 17.5 hours, providing a considerably longer therapeutic window and allowing once-daily administration at low doses. Tadalafil is therefore particularly attractive for patients seeking greater spontaneity in sexual activity (EAU, 2026).

Sildenafil versus vardenafil: Vardenafil has a pharmacokinetic profile broadly comparable to sildenafil, with an onset generally within approximately 30–60 minutes and a half-life of about 4–5 hours. Both agents demonstrate strong efficacy, although individual tolerability and patient preference influence treatment selection.

Sildenafil versus avanafil: Avanafil is characterized by a relatively rapid onset and may be administered approximately 15–30 minutes before sexual activity. Current evidence indicates broadly comparable efficacy among the major PDE5 inhibitors, while avanafil may have a somewhat favorable tolerability profile for certain adverse effects (ICSM, 2024; EAU, 2026).

Overall, PDE5 inhibitors should not be considered universally interchangeable from a patient-experience perspective. Sildenafil may be preferred when extensive clinical experience and established efficacy are priorities, whereas tadalafil may be advantageous when prolonged spontaneity is desired and avanafil may be attractive when rapid onset is particularly important.

Table 2. Comparison of Sildenafil With Other PDE5 Inhibitors

3.6 Limitations of Sildenafil Therapy

Despite its established efficacy, sildenafil does not provide a satisfactory response in every patient. Apparent nonresponse may result from inadequate dosing, incorrect administration, insufficient sexual stimulation, inappropriate timing, inadequate duration of treatment, severe endothelial dysfunction, neurogenic impairment, or advanced structural disease. Recent evidence emphasizes the importance of systematically reassessing these factors before labeling a patient as a true PDE5-inhibitor nonresponder (Nehra et al., 2025).

Adverse effects are generally dose-related and may include headache, flushing, dyspepsia, nasal congestion, dizziness, and visual disturbances. Differences among PDE5 inhibitors are partly related to their pharmacological profiles and tissue selectivity. Current comparative data indicate that all major PDE5 inhibitors have broadly similar efficacy, while individual adverse-effect patterns differ (ICSM, 2024).

Drug interactions remain an important limitation. Concomitant use of sildenafil with organic nitrates is contraindicated because excessive cGMP accumulation can cause potentially dangerous hypotension. Caution is also required with certain α-blockers, potent CYP3A4 inhibitors, and other medications that may alter systemic exposure or blood pressure. Appropriate cardiovascular assessment and medication review are therefore essential before treatment.

Finally, sildenafil addresses the erectile symptom but does not eliminate the underlying vascular, metabolic, neurological, endocrine, or psychological cause. Optimal management should therefore combine individualized PDE5-inhibitor therapy with modification of cardiovascular and metabolic risk factors, treatment of contributing diseases, and psychosexual interventions when indicated. Contemporary recommendations emphasize a personalized, patient-centered approach in which treatment selection considers efficacy, safety, patient preference, relationship factors, and treatment goals (ICSM, 2024).

Sildenafil remains a cornerstone therapy for ED because it effectively enhances endogenous NO–cGMP signaling and improves cavernosal smooth-muscle relaxation. Its efficacy extends across several clinically important populations, including men with diabetes, hypertension, metabolic abnormalities, and cardiovascular disease, although treatment response may be reduced when severe endothelial, vascular, or neurological dysfunction is present. Comparison with other PDE5 inhibitors highlights differences in onset, duration, dosing flexibility, and tolerability rather than major differences in fundamental mechanism. Consequently, successful sildenafil therapy depends not only on drug selection and dose optimization but also on appropriate patient evaluation, management of underlying comorbidities, and recognition of contraindications and drug interactions.

4. Sildenafil and the Cardiovascular System: Hemodynamics and Myocardial Protection

The cardiovascular effects of sildenafil extend beyond its established role in erectile dysfunction (ED). Because phosphodiesterase type 5 (PDE5) regulates cGMP signaling in vascular tissues, its inhibition can influence vascular tone, pulmonary hemodynamics, endothelial function, and several intracellular pathways involved in myocardial stress responses. Increasing experimental and observational evidence has therefore raised the possibility that PDE5 inhibition may have cardioprotective properties. However, the strength of evidence differs substantially between molecular studies, animal models, and human clinical trials. This distinction is particularly important when interpreting sildenafil as a potential cardiovascular therapeutic rather than simply a drug with favorable cardiovascular effects.

4.1 Cardiovascular Expression and Function of PDE5

PDE5 is a cGMP-specific phosphodiesterase expressed predominantly in vascular smooth muscle and other tissues involved in NO–cGMP signaling. Within the cardiovascular system, PDE5 participates in the regulation of vascular smooth-muscle tone by controlling the intracellular concentration and duration of cGMP signaling. Consequently, inhibition of PDE5 prolongs cGMP-mediated vasorelaxation and can modify vascular resistance and pulmonary vascular pressure (Francis et al., 2023).

The functional importance of PDE5 is closely linked to the NO–soluble guanylate cyclase (sGC)–cGMP–protein kinase G (PKG) pathway. Endothelial or neuronal NO activates sGC, increasing cGMP formation. cGMP subsequently activates PKG and promotes smooth-muscle relaxation through mechanisms involving intracellular calcium regulation, myosin light-chain phosphorylation, and ion-channel activity. PDE5 limits this signal by hydrolyzing cGMP. Sildenafil therefore does not directly replace NO signaling; rather, it prolongs and amplifies cGMP-dependent responses when the pathway is activated.

Recent cardiovascular pharmacology literature emphasizes that PDE5 is part of a broader network of cyclic-nucleotide phosphodiesterases that regulate compartmentalized signaling in the heart and vasculature. Alterations in this signaling network may contribute to pathological vascular remodeling, cardiac hypertrophy, and heart failure (Aye et al., 2023).

4.2 Hemodynamic Effects

Sildenafil produces systemic and pulmonary vasodilation primarily through enhancement of cGMP signaling in vascular smooth muscle. At clinically used doses, the reduction in systemic blood pressure is generally modest in otherwise stable individuals. Importantly, sildenafil does not behave like a conventional positive inotrope because PDE5 inhibition does not substantially increase myocardial cAMP signaling.

Clinical cardiovascular evidence indicates that sildenafil generally causes small reductions in systolic and diastolic blood pressure, with limited effects on heart rate. In appropriately selected patients, cardiac output is usually maintained rather than substantially increased or decreased. These effects are consistent with a predominantly vasodilatory rather than direct inotropic mechanism.

Pulmonary circulation represents a particularly important target because PDE5 is highly relevant to pulmonary vascular cGMP signaling. In pulmonary arterial hypertension, inhibition of PDE5 increases pulmonary vascular cGMP and promotes pulmonary vasodilation, thereby reducing pulmonary vascular resistance and improving pulmonary hemodynamics. Sildenafil's established role in pulmonary hypertension illustrates how a mechanism initially exploited for erectile dysfunction can become clinically relevant to cardiovascular medicine.

Sildenafil may also influence coronary vascular tone. Experimental and clinical studies suggest that PDE5 inhibition can promote coronary vasodilation and improve coronary flow reserve in selected settings. More recent experimental work has demonstrated dose-dependent effects of sildenafil on coronary flow and oxidative stress, supporting the concept that coronary microvascular signaling may contribute to its cardiovascular actions (Vukmirović et al., 2023).

Overall, the cardiovascular hemodynamic profile of sildenafil can be summarized as modest systemic vasodilation, pulmonary vasodilation, limited effects on heart rate, and preservation of cardiac output in most studied populations. However, these effects become clinically important when sildenafil is combined with other vasodilators, particularly organic nitrates.

4.3 Endothelial Function

Endothelial dysfunction is a common pathological feature of hypertension, diabetes, obesity, coronary artery disease, and heart failure. Reduced NO bioavailability, increased oxidative stress, impaired endothelial-dependent vasodilation, and vascular inflammation collectively contribute to abnormal vascular reactivity.

By preventing cGMP degradation, sildenafil can enhance the downstream effects of endogenous NO. This mechanism may improve endothelium-dependent vasodilation even when NO production is reduced but not completely abolished. Experimental and clinical investigations have consequently reported improvements in measures of vascular reactivity following PDE5 inhibition.

The potential importance of this effect extends beyond short-term vasodilation. Restoration of endothelial signaling may reduce vascular oxidative stress and improve the functional interaction between endothelial cells and vascular smooth muscle. Such effects could theoretically contribute to improved vascular homeostasis in patients with cardiometabolic disease.

A 2024 systematic review and meta-analysis provides clinically relevant support for the possibility of broader cardiovascular benefits. Across 16 observational studies involving more than 1.25 million individuals, PDE5 inhibitor use was associated with a lower risk of major adverse cardiovascular events and all-cause mortality. However, because most included studies were observational, the findings demonstrate association rather than definitive causation (Soulaidopoulos et al., 2024).

Thus, endothelial improvement represents a biologically plausible mechanism linking PDE5 inhibition with cardiovascular benefit, but it should not yet be interpreted as proof that sildenafil prevents cardiovascular disease.

Figure 2: Sildenafil effects on penile vasculature and cardiovascular system

4.4 Myocardial Ischemia and Reperfusion Injury

Myocardial ischemia followed by reperfusion produces a complex cascade of oxidative stress, calcium overload, mitochondrial dysfunction, inflammation, and cell death. Although reperfusion is essential for restoring coronary blood flow, the sudden return of oxygen and metabolic activity can itself aggravate myocardial injury. Limiting this ischemia–reperfusion injury is therefore an important objective of cardioprotective research.

Experimental studies have demonstrated that PDE5 inhibition can reduce myocardial injury following ischemia and reperfusion. Sildenafil has been shown in cellular and animal models to reduce cardiomyocyte necrosis and apoptosis and to decrease infarct size. These effects appear to involve increased cGMP signaling and activation of PKG-dependent survival pathways.

The proposed mechanism resembles aspects of pharmacological preconditioning, in which exposure to a stimulus before ischemia activates endogenous cellular defense mechanisms that subsequently reduce tissue injury. Sildenafil-induced cGMP/PKG signaling may initiate a protective network involving protein kinases, mitochondrial ion channels, and anti-apoptotic pathways.

Importantly, these findings are primarily derived from experimental models. Although they provide strong mechanistic evidence that PDE5 inhibition can influence myocardial resistance to ischemic stress, experimental cardioprotection cannot automatically be translated into reduced infarct size or mortality in patients.

4.5 Molecular Mechanisms of Cardioprotection

The cardioprotective effects attributed to sildenafil involve a signaling network extending beyond simple vasodilation. The central mechanism begins with PDE5 inhibition, increased intracellular cGMP, and activation of PKG.

cGMP/PKG signaling

Increased cGMP activates PKG, which functions as a major mediator of downstream cardioprotective signaling. PKG can regulate ion channels, contractile proteins, mitochondrial function, and kinase pathways involved in cellular survival. The importance of PKG is supported by experimental studies showing that pharmacological or genetic inhibition of PKG can markedly attenuate sildenafil-associated cardioprotection.

Protein kinase C and survival signaling

PKC-dependent signaling has also been implicated in PDE5 inhibitor-mediated cardioprotection. Activation of PKC may interact with mitochondrial and kinase pathways involved in ischemic preconditioning. This provides a potential mechanistic connection between PDE5 inhibition and endogenous myocardial defense mechanisms.

ERK/GSK3β pathways

The extracellular signal-regulated kinase (ERK) pathway represents another important component of sildenafil-mediated protection. Experimental studies demonstrate that sildenafil-associated PKG activation can stimulate ERK phosphorylation, with downstream effects involving glycogen synthase kinase-3β (GSK3β). Inhibition of these pathways reduces the protective response, supporting their functional role rather than merely representing secondary biochemical changes.

GSK3β is particularly relevant to mitochondrial integrity and cell survival. Its phosphorylation and functional inhibition have been associated with reduced mitochondrial injury during ischemia–reperfusion. Therefore, the PKG–ERK–GSK3β axis may represent an important molecular bridge between PDE5 inhibition and myocardial survival.

Mitochondrial KATP channels

Mitochondria are central regulators of ischemia–reperfusion injury because mitochondrial permeability transition, ATP depletion, calcium accumulation, and excessive reactive oxygen species generation can initiate irreversible cardiomyocyte injury. Experimental studies suggest that sildenafil-induced PKG signaling can promote opening of mitochondrial ATP-sensitive potassium channels (mitoKATP), a recognized component of ischemic preconditioning pathways.

Activation of mitoKATP channels may modify mitochondrial membrane potential and reduce susceptibility to permeability transition during reperfusion. This mechanism could help explain why sildenafil produces cardioprotective effects even when the drug is administered before an ischemic insult.

Anti-apoptotic signaling

Sildenafil has also been associated experimentally with increased expression of anti-apoptotic proteins and an increased Bcl-2/Bax ratio. Together with PKG, ERK, and mitochondrial signaling, these effects may reduce activation of apoptotic pathways and improve cardiomyocyte survival following ischemic stress.

Figure 3: Proposed molecular mechanisms of myocardial protection

4.6 Potential Effects on Cardiac Remodeling and Heart Failure

Cardiac remodeling involves structural and functional changes that develop in response to chronic pressure or volume overload, myocardial injury, neurohormonal activation, and metabolic stress. Because cGMP/PKG signaling regulates vascular tone, myocardial hypertrophy, fibrosis, and cellular stress responses, PDE5 inhibition has been investigated as a potential strategy for modifying pathological cardiac remodeling.

Preclinical studies suggest that PDE5 inhibition may attenuate pressure-overload-associated hypertrophy and improve myocardial relaxation. In heart failure with reduced ejection fraction (HFrEF), small clinical studies have reported improvements in selected measures of ventricular function, pulmonary hemodynamics, and exercise capacity. A contemporary review of cardiac PDE biology similarly identifies PDE5 inhibition as a promising strategy in HFrEF, although larger trials remain necessary for definitive therapeutic conclusions (Aye et al., 2023).

The situation is considerably less consistent in heart failure with preserved ejection fraction (HFpEF). Clinical trials have not established a consistent improvement in exercise capacity or clinical outcomes with sildenafil in unselected HFpEF populations. This discrepancy may reflect substantial biological heterogeneity within HFpEF, including differences in pulmonary vascular disease, right-ventricular dysfunction, endothelial dysfunction, and cGMP availability.

Sildenafil is more firmly established in pulmonary arterial hypertension, where reduction of pulmonary vascular resistance is a central therapeutic objective. Its ability to modify pulmonary vascular tone may also influence right-ventricular afterload and ventricular–vascular coupling.

Thus, sildenafil may have therapeutic relevance to selected cardiovascular phenotypes, but PDE5 inhibition should not currently be considered a universal heart-failure therapy.

4.7 Translational Gap

One of the most important issues in evaluating sildenafil as a cardiovascular drug is the discrepancy between strong mechanistic evidence and limited definitive clinical evidence.

At the cellular level, sildenafil activates cGMP/PKG signaling and influences ERK, GSK3β, mitochondrial channels, oxidative stress, and apoptotic pathways. These experiments establish biological plausibility.

At the animal level, PDE5 inhibition has repeatedly demonstrated reductions in myocardial infarct size, cardiomyocyte apoptosis, ischemia–reperfusion injury, pathological hypertrophy, and selected forms of ventricular dysfunction. These results provide stronger evidence that the molecular mechanisms can produce meaningful tissue-level effects.

At the human clinical level, however, evidence remains heterogeneous. Some small trials demonstrate improvements in hemodynamics, endothelial function, ventricular performance, or exercise capacity, whereas larger or more rigorously controlled studies have not consistently demonstrated improvement in major clinical outcomes. A contemporary review of PDE5 inhibitor cardiovascular studies concluded that preclinical evidence is compelling but that translation into positive clinical trials has been inconsistent (Jovin et al., 2023).

This distinction is critical because observational studies suggesting reduced cardiovascular events cannot establish that sildenafil itself produces the benefit. A 2024 meta-analysis found lower MACE and mortality among PDE5 inhibitor users, but residual confounding, treatment-selection bias, differences in baseline cardiovascular health, and the healthy-user effect remain possible explanations (Soulaidopoulos et al., 2024).

The Princeton IV Consensus therefore supports a cardiovascular-risk-based approach to men with ED and emphasizes appropriate cardiovascular assessment rather than treating PDE5 inhibitors as established cardioprotective drugs (Kloner et al., 2024).

Sildenafil exerts important cardiovascular actions through inhibition of PDE5 and enhancement of the NO–cGMP–PKG pathway. Its acute cardiovascular effects include modest systemic vasodilation and clinically meaningful pulmonary vasodilation, while experimental studies indicate additional effects on endothelial function, mitochondrial signaling, myocardial ischemia–reperfusion injury, apoptosis, and cardiac remodeling. The molecular evidence supports a cardioprotective network involving cGMP/PKG, PKC, ERK, GSK3β, mitoKATP channels, mitochondrial stabilization, and anti-apoptotic signaling.

Nevertheless, the strongest evidence for direct myocardial protection remains preclinical. Human studies provide encouraging but inconsistent evidence, and observational associations between PDE5 inhibitor use and improved cardiovascular outcomes cannot establish causality. Therefore, the current scientific position is best described as mechanistically compelling, clinically promising, but not yet definitive for cardioprotection. This translational gap represents an important priority for future randomized cardiovascular trials.

Table 3. Cardiovascular Effects and Evidence From Clinical Studies

5. Clinical Safety, Contraindications, Drug Interactions, and Patient Selection

Sildenafil has an extensive clinical safety record and is generally well tolerated when administered at recommended doses to appropriately selected patients. Its adverse-effect profile is largely related to systemic vasodilation and, to a lesser extent, inhibition of PDE isoenzymes other than PDE5. However, cardiovascular status, concomitant medications, organ function, and ocular history should be considered before treatment. Contemporary evidence emphasizes that sildenafil should not simply be regarded as an erectile dysfunction medication; in men with erectile dysfunction, treatment should occur within an assessment of overall cardiovascular health and the safety of sexual activity (Salonia et al., 2025; Shen et al., 2026).

5.1 General Safety Profile

The adverse effects of sildenafil are predominantly mild, transient, and dose related. The most frequently reported reactions include headache, flushing, dyspepsia, nasal congestion, dizziness, and visual disturbances. According to the updated European Association of Urology evidence synthesis, headache and flushing are among the most frequent adverse events with sildenafil, while dyspepsia, nasal congestion, dizziness, and abnormal vision occur less commonly. These effects generally reflect systemic vasodilation or the pharmacological activity of sildenafil at related phosphodiesterase isoenzymes (Salonia et al., 2025).

Headache and facial flushing are particularly characteristic because inhibition of PDE5 increases cGMP-mediated vasodilation beyond the corpus cavernosum. Dyspepsia may result from smooth-muscle effects within the gastrointestinal tract, whereas nasal congestion is associated with vasodilation of the nasal mucosa. Dizziness is generally mild but may become clinically relevant in individuals with low baseline blood pressure or when sildenafil is combined with other vasodilating drugs.

Visual symptoms, including altered color perception, increased brightness, blurred vision, or photophobia, are usually transient and are related partly to weak inhibition of retinal PDE6. Recent real-world pharmacovigilance data demonstrate that ocular adverse-event reporting occurs with PDE5 inhibitors, including sildenafil, although these reports cannot establish causality or absolute incidence. Therefore, patients should be advised to report persistent or sudden visual changes promptly (Zhang et al., 2024).

5.2 Cardiovascular Safety

Sildenafil produces systemic vasodilation and may cause modest reductions in systolic and diastolic blood pressure. In most appropriately selected patients, these changes are clinically limited and do not result in significant impairment of cardiac performance. Nevertheless, the magnitude of the blood-pressure response can increase when sildenafil is administered with other vasodilators or antihypertensive agents.

Orthostatic hypotension is therefore an important consideration, particularly in older individuals, patients receiving multiple antihypertensive drugs, and those with autonomic dysfunction or reduced intravascular volume. Recent pharmacovigilance evidence indicates that hypotension signals are particularly important when PDE5 inhibitors are combined with other pulmonary vasodilators, supporting careful assessment of the complete cardiovascular medication regimen rather than evaluation of sildenafil in isolation (2026).

In patients with stable coronary artery disease, appropriately prescribed sildenafil is generally considered compatible with sexual activity when the patient's cardiovascular functional capacity is adequate. The major concern is not sildenafil-induced myocardial ischemia in stable patients but the possibility that sexual activity itself may exceed the patient's cardiovascular reserve. Consequently, assessment of exercise tolerance, symptoms, cardiovascular comorbidities, and current medications is essential before prescribing.

Available clinical and observational evidence has not demonstrated a consistent increase in myocardial infarction or fatal cardiovascular events attributable to sildenafil when used according to prescribing recommendations. However, pharmacovigilance databases contain reports of serious cardiovascular events. Such databases are useful for detecting safety signals but cannot establish causality because of reporting bias, confounding by indication, comorbidities, and incomplete exposure information (Zhu et al., 2025).

Arrhythmia considerations are similarly patient specific. Sildenafil does not generally produce clinically important electrophysiological instability at therapeutic doses, but treatment should be approached cautiously in patients with unstable cardiovascular disease or high-risk arrhythmias. Thus, cardiovascular stability and functional capacity are more important determinants of appropriate use than the mere presence of cardiovascular disease.

5.3 Nitrate Interaction: The Major Contraindication

The interaction between sildenafil and organic nitrates represents the most clinically important contraindication. Nitrates include nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate, as well as other nitric oxide–donating preparations. Sildenafil potentiates the NO–sGC–cGMP pathway, whereas nitrates increase endogenous NO availability and consequently stimulate cGMP production. Simultaneous administration therefore produces both increased cGMP synthesis and reduced cGMP degradation.

The resulting excessive accumulation of cGMP in vascular smooth muscle can cause marked vasodilation and profound hypotension. In patients with coronary artery disease, severe hypotension may additionally compromise coronary perfusion and potentially precipitate myocardial ischemia. This pharmacodynamic interaction remains a fundamental contraindication despite the otherwise favorable cardiovascular safety profile of sildenafil (Kloner et al., 2024; Salonia et al., 2025).

The nitrate interaction should therefore be explicitly highlighted in clinical algorithms and prescribing tables. Patients receiving nitrate therapy should not be given sildenafil for erectile dysfunction, and clinicians should establish whether patients use scheduled, intermittent, sublingual, transdermal, or other nitrate formulations before prescribing.

5.4 Interactions With Other Cardiovascular Drugs

Unlike nitrates, most commonly prescribed cardiovascular drugs do not constitute absolute contraindications to sildenafil. Nevertheless, additive blood-pressure lowering may occur with α-blockers and antihypertensive agents. Patients receiving α-blockers may experience symptomatic hypotension, particularly when sildenafil is initiated at higher doses or administered before the patient has become stable on α-blocker therapy. Conservative dose selection and clinical monitoring are therefore appropriate.

Sildenafil can generally be used with several classes of antihypertensive medication, including β-blockers, calcium-channel blockers, and diuretics, although additive hypotensive effects should be anticipated in susceptible patients. The updated clinical literature supports individualized assessment rather than routine exclusion of patients receiving antihypertensive therapy (Salonia et al., 2025; Shen et al., 2026).

An additional consideration involves CYP3A4-mediated drug interactions. Sildenafil is predominantly metabolized through CYP3A4, and potent CYP3A4 inhibitors can increase systemic sildenafil exposure. This may enhance vasodilatory adverse effects and increase the likelihood of hypotension, headache, flushing, or other dose-related reactions. Consequently, medication reconciliation should include prescription drugs, over-the-counter medicines, and relevant supplements before sildenafil initiation.

Recent pharmacovigilance studies further emphasize that drug combinations can influence the safety profile of PDE5 inhibitors. In patients receiving sildenafil for pulmonary arterial hypertension, combinations with other pulmonary vasodilators have generated hypotension signals, illustrating the importance of evaluating additive pharmacodynamic effects in patients receiving multidrug cardiovascular therapy (2026).

5.5 Contraindications and Precautions

The principal contraindication to sildenafil is concomitant treatment with organic nitrates or other clinically significant NO-donor therapy. Additional precautions are required in patients with unstable or high-risk cardiovascular disease.

Patients with unstable angina, uncontrolled hypertension, severe hypotension, high-risk arrhythmias, decompensated heart failure, or other unstable cardiovascular conditions should generally undergo cardiovascular evaluation and stabilization before treatment for ED. Similarly, individuals with recent major cardiovascular events require individualized assessment rather than automatic initiation of sildenafil.

Organ dysfunction may also modify sildenafil exposure. Severe hepatic or renal impairment can reduce drug clearance and increase systemic exposure, potentially increasing adverse effects; therefore, dose selection should follow current product-specific prescribing recommendations.

Visual disorders require additional consideration. Transient visual disturbances are recognized adverse effects of sildenafil, and real-world pharmacovigilance analyses have identified reports of ocular adverse events among PDE5 inhibitor users. Rare reports of serious retinal or optic-nerve events have also been described, although causality is difficult to establish because ED and its associated cardiovascular risk factors may themselves predispose patients to ocular vascular disease (Zhang et al., 2024; Chawla et al., 2025).

Accordingly, patients should be instructed to discontinue use and seek urgent ophthalmologic assessment if they develop sudden loss of vision, persistent major visual disturbance, or other acute ocular symptoms. This precaution is particularly important because rare serious ocular events differ substantially from the mild and transient visual changes typically associated with therapeutic sildenafil exposure.

Table 4. Adverse Effects, Contraindications, and Clinically Important Drug Interactions