Nitric Oxide as a NOvel’ Therapy for Gastrointestinal Ulcers?

Abstract & Commentary

Synopsis: Drugs that release nitric oxide have been shown to prevent ulcers and accelerate ulcer healing in animals. This large, case-control study demonstrates that oral or transdermal nitrosovasodilators are independently associated with a reduced risk of upper gastrointestinal bleeding.

Source: Lanas A, et al. N Engl J Med 2000;343:834-839.

Lanas and colleagues studied the relationship between medications that release nitric oxide (oral or transdermal preparations of nitroglycerin), medications that promote ulcers (low-dose aspirin, high-dose aspirin, and other nonsteroidal anti-inflammatory drugs [NSAIDS]), anti-acid agents (H2 receptor antagonists and omeprazole), and the risk for developing upper gastrointestinal (GI) bleeding. They performed a case-control study of 1122 consecutive patients admitted with upper GI bleeding to one of four general hospitals in Spain. The 2231-patient control group consisted of 1109 patients hospitalized for other reasons and 1122 outpatients from the same region. Control subjects were chosen to achieve frequency matching with the patients according to sex and age.

As expected, the use of NSAIDS was associated with an increased risk of bleeding (odds ratio, 7.4 for NSAIDS other than low-dose aspirin and 2.4 for low-dose aspirin), and anti-secretory therapy was protective (odds ratio, 0.6). Omeprazole, a proton-pump inhibitor, was more effective than H2-receptor antagonists. Interestingly, the use of nitrosovasodilators was protective as well, with an odds ratio of 0.6 and a 95% confidence interval of 0.4-0.8. Despite the antiplatelet effects of nitric oxide, nitrosovasodilators appeared to prevent GI bleeding.

COMMENT BY MARK T. GLADWIN, MD

Nitric oxide is a free-radical gas molecule produced endogenously by the nitric oxide synthase enzyme systems, and plays a critical role in the regulation of blood flow, immune function, and cellular signal transduction. Recent data suggest that nitric oxide increases gastric mucosal blood flow and inhibits leukocyte adherence to the GI microvasculature. These properties result in reduction in ulcerogenesis and improvement in ulcer healing in rats treated with oral or intravenous nitroglycerin. A nitric oxide-releasing aspirin product has even been developed to reduce ulcer formation. Critically ill patients are highly susceptible to gastric and duodenal erosion, ulceration, and bleeding, particularly in the presence of coagulopathy and the need for mechanical ventilation. While antisecretory therapies are protective, they increase the risk of nosocomial pneumonia, and breakthrough bleeding is common. For these reasons, new therapies to reduce the incidence of GI bleeding in the ICU are needed. These data suggest that nitric oxide releasing compounds, taken orally or transdermally—and, thus, suggesting that intravenous therapy would be effective—reduce the clinical risk of GI hemorrhage. Studies in ICU patients at risk for such bleeding should be undertaken in order to determine whether nitroglycerin preparations should be administered daily, enterally or transdermally, to mechanically ventilated ICU patients. Will these therapies be effective in this population and will they demonstrate additive or synergistic effects with antisecretory therapy? (Dr. Gladwin is Senior Research Fellow, Department of Critical Care Medicine, National Institutes of Health, Bethesda, Md.)