Does sildenafil increase nitric oxide? This is a common question among patients prescribed this medication for erectile dysfunction or pulmonary arterial hypertension. Whilst sildenafil (Viagra, Revatio) plays a crucial role in enhancing erectile function and improving blood flow, it does not directly increase nitric oxide production. Instead, sildenafil works by amplifying the effects of nitric oxide already present in the body. Understanding this distinction is essential for safe and effective use, particularly given the serious risks associated with combining sildenafil with nitrate medications. This article explains the precise mechanism of action, the relationship between sildenafil and nitric oxide, and important safety considerations.

How Sildenafil Works in the Body

Sildenafil belongs to a class of medications called phosphodiesterase type 5 (PDE5) inhibitors. It is primarily prescribed for erectile dysfunction (ED) as Viagra (25-100 mg as needed, maximum once daily) and pulmonary arterial hypertension as Revatio (20 mg three times daily). Understanding its mechanism requires knowledge of the body's natural erectile response pathway.

When sexual stimulation occurs, nerve endings in the penis release nitric oxide (NO), which activates an enzyme called guanylate cyclase. This enzyme increases levels of cyclic guanosine monophosphate (cGMP), a chemical messenger that relaxes smooth muscle cells in the blood vessels of the corpus cavernosum. This relaxation allows increased blood flow into the penis, resulting in an erection. However, another enzyme—phosphodiesterase type 5—naturally breaks down cGMP, which eventually causes the erection to subside.

Sildenafil works by selectively inhibiting PDE5, thereby preventing the breakdown of cGMP. This allows cGMP to accumulate and remain active for longer periods, enhancing and prolonging the smooth muscle relaxation and blood flow necessary for achieving and maintaining an erection. Importantly, sildenafil does not work in isolation; it requires the presence of nitric oxide to initiate the cascade. Without sexual stimulation and the subsequent release of nitric oxide, sildenafil will not produce an erection.

The medication is typically taken orally, with effects beginning within 30 to 60 minutes (though high-fat meals may delay onset) and lasting approximately four to six hours. Sildenafil is absorbed through the gastrointestinal tract and metabolised primarily in the liver by cytochrome P450 enzymes, particularly CYP3A4 and CYP2C9. This metabolic pathway means caution is needed with strong CYP3A4 inhibitors, alpha-blockers, and grapefruit juice. Moderate alcohol consumption is advised as excessive amounts may increase the risk of side effects.

The Relationship Between Sildenafil and Nitric Oxide

A common misconception is that sildenafil directly increases nitric oxide production in the body. In reality, sildenafil does not increase nitric oxide levels; rather, it enhances the effects of nitric oxide that is already present. This distinction is clinically important for understanding both the therapeutic action and safety profile of the medication.

Nitric oxide acts as the initial trigger in the erectile response. When released from nerve endings and endothelial cells lining blood vessels, it binds to guanylate cyclase receptors, initiating the production of cGMP. Sildenafil's role begins after this point—it prevents the enzymatic degradation of cGMP by blocking PDE5. By doing so, it amplifies and prolongs the downstream effects of whatever nitric oxide is naturally present, rather than generating additional nitric oxide itself.

This mechanism explains why sildenafil requires sexual arousal to be effective. Without the natural release of nitric oxide triggered by sexual stimulation, there is no cGMP production for sildenafil to preserve. The medication essentially acts as a facilitator or enhancer of the body's existing nitric oxide-cGMP pathway, not as an independent source of nitric oxide.

From a broader physiological perspective, nitric oxide plays multiple roles beyond erectile function, including regulation of blood pressure, immune response, and neurotransmission. Sildenafil's selective action on PDE5 means it primarily affects tissues where this enzyme is abundant—notably the corpus cavernosum of the penis and pulmonary vasculature. While sildenafil may cause small, transient reductions in blood pressure in some users, it has minimal direct impact on systemic nitric oxide levels. This selectivity contributes to its therapeutic utility, though caution is advised in people with hypotension or those taking antihypertensive medications.

Why Nitrates and Sildenafil Should Never Be Combined

The combination of sildenafil with nitrate medications represents a potentially life-threatening drug interaction that is absolutely contraindicated. Nitrates—including glyceryl trinitrate (GTN), isosorbide mononitrate, and isosorbide dinitrate—are commonly prescribed for angina and other cardiovascular conditions. They work by releasing nitric oxide, which increases cGMP production and causes vasodilation, thereby reducing cardiac workload and relieving chest pain.

When sildenafil is taken alongside nitrates, the result is a synergistic and profound drop in blood pressure. The nitrate medication floods the system with nitric oxide, dramatically increasing cGMP production. Simultaneously, sildenafil blocks the breakdown of this cGMP by inhibiting PDE5. The combined effect produces excessive vasodilation throughout the body, leading to severe hypotension that can result in dizziness, fainting, myocardial infarction, stroke, or even death.

This interaction is not merely theoretical—it has been well-documented in clinical practice and is emphasised in MHRA guidance and product information. The hypotensive effect can occur with any formulation of nitrates, including sublingual sprays, tablets, patches, and ointments. According to the BNF and MHRA guidance, sildenafil should not be used within 24 hours of taking any nitrate medication, and nitrates should not be administered within 24 hours of sildenafil use (or 48 hours for longer-acting PDE5 inhibitors like tadalafil).

Similarly, sildenafil is contraindicated with riociguat (a soluble guanylate cyclase stimulator) and caution is needed with nicorandil (a nitrate donor). Patients prescribed sildenafil must be explicitly counselled about these interactions. Those with cardiovascular disease who may require emergency nitrate therapy should inform all healthcare providers—including paramedics and emergency department staff—that they have recently taken sildenafil. If chest pain occurs after taking sildenafil, patients should call 999 immediately and inform clinicians about recent PDE5 inhibitor use. Recreational use of nitrate-containing substances (such as amyl nitrite 'poppers') alongside sildenafil poses the same serious risks.

Clinical Evidence on Sildenafil's Effects on Nitric Oxide

Extensive clinical research has examined sildenafil's pharmacological effects, consistently demonstrating that the drug does not directly alter nitric oxide synthesis or baseline levels. Rather, evidence confirms its mechanism as a selective PDE5 inhibitor that potentiates existing nitric oxide signalling pathways.

Pivotal trials establishing sildenafil's efficacy for erectile dysfunction, including studies published in the late 1990s and early 2000s, measured various cardiovascular and biochemical parameters. These studies showed that whilst sildenafil enhances erectile function in the presence of sexual stimulation (and thus endogenous nitric oxide release), it does not independently increase circulating nitric oxide metabolites or significantly affect nitric oxide synthase enzyme activity. Plasma measurements of nitric oxide breakdown products (nitrites and nitrates) remain largely unchanged with sildenafil monotherapy in the absence of exogenous nitric oxide donors.

Research into sildenafil's use for pulmonary arterial hypertension has provided additional insights. Studies demonstrate that sildenafil improves pulmonary haemodynamics by enhancing the effects of endogenous nitric oxide in pulmonary vasculature, where PDE5 is highly expressed. The therapeutic benefit derives from preventing cGMP degradation rather than increasing nitric oxide production.

Important safety data from post-marketing surveillance and case reports have reinforced the critical nature of the sildenafil-nitrate interaction. Documentation of severe hypotensive episodes when these medications are combined has led to prominent warnings in the British National Formulary (BNF) and Summary of Product Characteristics (SmPC). Common adverse effects include headache, flushing, dyspepsia, and nasal congestion—effects largely attributable to mild vasodilation from enhanced nitric oxide-cGMP signalling in various tissues. Serious but rare adverse effects requiring immediate medical attention include priapism (erection lasting >4 hours), sudden vision loss (possible non-arteritic anterior ischaemic optic neuropathy), and sudden hearing loss. Patients experiencing chest pain whilst taking sildenafil should call 999 immediately and inform clinicians of their medication use before any treatment is administered. Suspected adverse reactions should be reported via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk).

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