Tolerance of Rodents to an Intravenous Bolus Injection of Sodium Nitrate in a High Concentration

SIMPLE SUMMARY: Nitrate is found in many foods and is a common metabolite that is supplied mostly through the diet. Recently, we have found that an analog of this compound, labeled with the stable isotope (non-radioactive) nitrogen-15, is a potentially useful contrast agent for magnetic resonance imaging (MRI), as it does not include a metal component as most other MRI contrast agents. This analog was previously shown with a very high magnetic resonance signal, which is relatively long-lasting, when combined with the new adjunct technology to MRI called hyperpolarization. Prior to serving as a contrast agent for MRI in patients, this agent needs to be tested and validated in small animals. As a prerequisite to such studies, one must ensure that the injection of the naturally abundant agent (not labeled with any isotopes) will be tolerated by the animals. The purpose of the current study was to evaluate the tolerance to an intravenous injection of sodium nitrate in rats and mice, as MRI contrast agents are routinely administered in this way. We have found that a high dose of sodium nitrate can be safely injected into rats and mice. This result opens the way for preclinical MRI studies with sodium nitrate. ABSTRACT: Nitrate, the inorganic anion NO(3)(−), is found in many foods and is an endogenous mammalian metabolite, which is supplied mostly through the diet. Although much is known about the safety of sodium nitrate when given per os, methodological safety data on intravenous bolus injection of sodium nitrate to rodents are lacking. Recently, we have proposed a new use for nitrate, as a contrast agent for magnetic resonance imaging that will be metal free and leave no traces in the body and the environment further to the imaging examination. It was shown that a stable isotope-labelled analog of this ion ((15)NO(3)(−)), in a sodium nitrate solution form and hyperpolarized state, produces a high magnetic resonance signal with prolonged visibility. Therefore, sodium nitrate was targeted for further preclinical development in this context. In the absence of methodological safety data on the potential effects of a high concentration sodium nitrate bolus intravenous injection into rodents, we carried out such an investigation in mice and rats (n = 12 of each, 6 males and 6 females in each group, altogether 24 animals). We show here that an intravenous bolus administration of sodium nitrate at a concentration of 150 mM and a dose of 51 mg/Kg does not lead to adverse effects in mice and rats. This is the first investigation of the tolerance of rodents to an intravenous injection of sodium nitrate.