Consistent gastric pH-dependent effects of suppressors of gastric acid secretion on the antihypertensive responses to oral nitrite

Proton pump inhibitors (PPI) are suppressors of gastric acid secretion (SGAS) that decrease gastric nitric oxide (NO) formation from nitrite and increase the cardiovascular risk. However, H2 receptor antagonists (H2RA) are considered safer than PPIs. We challenged this notion and hypothesized that both omeprazole (PPI) and ranitidine (H2RA) attenuate the responses to oral nitrite because both drugs increase gastric pH and therefore could decrease nitrite-derived NO formation in the stomach. We examined the blood pressure responses to oral nitrite in hypertensive rats treated with omeprazole, ranitidine, or vehicle. Chemiluminensce-based assays were used to measure gastric NO formation, plasma and gastric concentrations of nitrite, nitrate, and nitrosylated species (RXNO) to clarify the mechanism involved in the effects of SGAS on the responses to oral nitrite. Both drugs increased gastric pH, impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. These findings were reproduced in a second study using sodium acetate buffers at pH 3.5, 4.5, and 5.5 to mimic gastric pH found with vehicle, ranitidine, and omeprazole, respectively. Increasing gastric pH impaired oral nitrite-induced hypotensive responses, gastric NO formation, and blunted the increases in circulating RXNO concentrations, but not in circulating nitrite and nitrate concentrations. Our results clearly indicate that SGAS impair nitrite-induced gastric formation of NO and vasoactive RXNO in a pH-dependent manner, thus resulting in impaired responses to oral nitrite. These findings may have several clinical implications, particularly to patients with cardiovascular diseases.