However, reduced acidity hinders the gastric bioactivation of nitrite into NO: without a highly acidic environment, absorbed nitrite remains largely in the form of nitrite in the plasma, which alone has a much less vasodilatory effect than nitrite, which is readily converted into NO in the stomach. In practice, therefore, pantoprazole decreases the effectiveness of oral nitrite because it attenuates its transformation into the active ingredient (NO) responsible for the biological effects.
Scientific evidence on pantoprazole–nitrite interaction
Preclinical studies have clearly demonstrated the influence of gastric acidity on the effect of nitrite. For example, in a study on rats, the administration of omeprazole (a PPI) or ranitidine (an H₂ antagonist) before nitrite canceled the hypotensive effects of oral nitrite: the increase in gastric pH due to these drugs counteracted the ability of nitrite to generate NO, abolishing the usual reduction in blood pressure. This pH-dependent effect is attributed to the fact that much of the vasodilatory action of oral nitrite derives from gastric formation of NO/S-nitrosothiols, a process that is blocked if the stomach is not acidic enough. Consistently, an increase in blood pressure was observed in rats chronically treated with PPIs, suggesting a reduced availability of endogenous NO from dietary nitrite (a potential mechanism by which prolonged use of PPIs could contribute to hypertensive risk).
Clinical studies confirm these findings. A controlled crossover trial in healthy volunteers (Montenegro et al., 2017) evaluated the cardiovascular effects of oral nitrite with and without gastric acid suppression. Participants received oral sodium nitrite (0.3 mg/kg) after pretreatment with either placebo or esomeprazole (a PPI, 40 mg three times a day). The results are clear: after placebo, nitrite reduced systolic blood pressure by approximately 6 ± 1.3 mmHg, while after esomeprazole the hypotensive effect was practically abolished. It is important to underline that the plasma concentrations of nitrite and its metabolites (nitrates and nitroso derivatives) were similar in both cases. In other words, the PPI did not prevent nitrite from being absorbed and circulating in the blood, but prevented its effective "activation". A further experiment in the same study showed that intravenous infusions of nitrite (which bypass the stomach) at plasma concentrations similar to those obtained orally did not cause any drop in blood pressure. This indicates that nitrite itself, in circulation, does not significantly lower blood pressure unless it is transformed locally into NO (as instead occurs in the acidic stomach). The authors conclude that an acidic gastric environment is necessary for the acute hypotensive effect of oral nitrite. These scientific evidences support the idea that the reduction of gastric acidity by pantoprazole decreases the gastrointestinal conversion of nitrite into bioactive compounds, thus attenuating its systemic pharmacological effects without drastically altering the amount absorbed. In summary, the presence of acid in the stomach acts as a key catalyst to release nitric oxide from ingested nitrite, and drugs such as pantoprazole interfere with this step.
Practical advice on sequence and timing of administration
To optimize the absorption and especially the efficacy of oral sodium nitrite, it is advisable to avoid concomitant suppression of gastric acidity. In practice:
• Do not take pantoprazole immediately before (or together with) sodium nitrite. Pantoprazole takes 1-2 hours to inhibit the active pumps, but once activated the antisecretory effect lasts for many hours; taken before nitrite, it will reduce acidity just when nitrite reaches the stomach, hindering its conversion into NO.
