Nitrite ion : its role in vasoregulation and host defenses

Abstract

Nitrite and nitrate are distributed throughout the human body, with especially high levels being present in saliva. Until recently, these anions were considered merely to be inert end-products of the oxidation of endogenous nitric oxide (NO). This thesis is part of a rapidly growing field of research which now reveals, surprisingly, that the nitrite ion can be reduced chemically to NO in both blood and tissues. Such NO may play an important role, e.g., in vasoregulation and host defenses against bacteria, similar to that played by NO formed from L-arginine via the action of NO synthases.

A major aim here has been to characterize the reduction of nitrite to NO and other nitrogen oxides in the stomach, as well as the actions of nitrite in the gastric environment, where the levels of this anion are exceptionally high, due to reduction of nitrate by symbiotic bacteria in the oral cavity. First, however, we explored the possibility that very low levels of nitrite, similar to those present in blood and tissues, can be converted into vasodilatory levels of NO.

In experiments employing rings of rat aortic tissue, we demonstrated that when the pH of the buffer solution is lowered to resemble a situation of metabolic acidosis or ischemia, nitrite is reduced to NO with concomitant vasorelaxation.

Next, we found that when delivered into the acidic stomach of rats, human saliva containing nitrite causes rapid mucosal vasodilatation and enhances the generation of mucus. These effects are dependent on cyclic guanosine monophosphate (cGMP) and, again, paralleled by formation of NO.

Moreover, we demonstrated that the high levels of NO and other nitrogen oxides generated by a mixture of human saliva and gastric juice are bactericidal towards a laboratory strain of Escherichia coli . Similar results are obtained when NO itself is delivered via diffusion through a silicone balloon attached to a gastric tube.

In the final study on human subjects we showed that continuous delivery of nitrite-containing saliva is required to maintain high intragastric levels of NO. Indeed, in intubated, critically ill patients, who do not swallow their saliva, gastric NO is virtually absent. However, upon intragastric administration of nitrite, a normal level of gastric NO is rapidly restored in these individuals.

Together, these observations clearly illustrate the physiological relevance of the newly discovered pathway for the generation of NO by chemical reduction of nitrite. In the local gastric environment NO may have important protective roles to play through stimulating gastric mucosal blood flow and mucus production, as well as by killing ingested pathogens. Critically ill patients have extremely low gastric levels of NO, because they cannot swallow their saliva. These patients are prone to develop stress ulcers and their stomachs are rapidly colonized by bacteria, which may result in serious infections, including pneumonia. Future studies will reveal whether the simple procedure for restoring intragastric NO described here can be used to reduce the incidence of these serious complications in such patients.

Under conditions of ischemia and metabolic stress, reduction of nitrite to vasodilatory levels of NO can also occur systemically. We propose that a continuous intake of nitrate-containing food, e.g., vegetables may help to maintain tissue levels of nitrite and NO at adequate levels even when endogenous enzymatic synthesis of NO is disturbed. If true, these considerations could have a profound impact on our view of the role of diet and commensal bacteria in the regulation of normal physiological processes and prevention of cardiovascular disease.