Use of nitrite salts for the treatment of cardiovascular conditions

Abstract

It has been surprisingly discovered that administration of pharmaceutically-acceptable salts of nitrite is useful in the regulation of the cardiovascular system. It has also been surprisingly discovered that nitrite is reduced to nitric oxide in vivo, and that the nitric oxide produced thereby is an effective vasodilator. These effects surprisingly occur at nitrite doses that do not produce clinically significant methemoglobinemia. These discoveries now enable methods to prevent and treat conditions associated with the cardiovascular system, for example, high blood pressure, pulmonary hypertension, cerebral vasospasm and tissue ischemia-reperfusion injury. These discoveries also provide methods to increase blood flow to tissues, for example, to tissues in regions of low oxygen tension.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 485,959, filed Jul. 9, 2003, and No. 60 / 511,244, filed Oct. 14, 2003, both of which are incorporated herein by reference in their entirety.BACKGROUND OF THE DISCLOSURE [0002] The last decade has seen an increase in the understanding of the critical role nitric oxide as a blood vessel dilator contributing to the regulation of blood flow and cardiovascular homeostasis. Nitric oxide may be oxidized in blood to nitrite (NO2−), an anion considered to be an inert metabolic end product of such nitric oxide oxidation. In vivo plasma levels of nitrite have been reported to range from 150 to 1000 nM, and the nitrite concentration in aortic ring tissue has been reported to be in excess of 10,000 nM Rodriguez et al., Proc Natl Acad Sci USA, 100, 336-41, 2003; Gladwin et al., Proc Natl Acad Sci USA, 97, 9943-8, 2000; and Rassaf et al., Nat Med, 9, 481-3, 2003). This potential...

AI Technical Summary

Benefits of technology

[0008] It has been surprisingly discovered that administration of pharmaceutically-acceptable salts of nitrite is useful in the regulation of the cardiovascular system. It has also been surprisingly discovered that nitrite is reduced to nitric oxide in vivo, and that the nitric oxide produced thereby is an effective vasodilator. These effects surprisingly occur at doses that do not produce clinically significant methemoglobinemia. These discoveries now enable methods to prevent and treat conditions associated with the cardiovascular system, for example, high blood pressure, pulmonary hypertension, cerebral vasospasm and tissue ischemia-reperfusion injury. These discoveries also provide methods to increase blood flow to tissues, for example, to tissues in regions of low oxygen tension. It is particularly surprising that the nitrite does not need to be applied in an acidified condition in order for it to be effective in regulating the cardiovascular system, and more particularly to act as a vasodilator in vivo.

[0009] It has been demonstrated by the inventors that nitrite can serve as a vasodilator in humans at much lower concentrations (as low as 0.9 μM) than have been used in the past for cyanide poisoning. The mechanism is believed to involve a reaction of nitrite with deoxygenated hemoglobin and red blood cells, to produce the vasodilating gas nitric oxide. This potent biological effect is observed at doses of nitrite that do not produce clinically significant methemoglobininemia (for instance, less than 20%, more preferably less than 5% methemoglobin in the subject).

[0012] The present disclosure additionally provides a method for increasing blood flow to a tissue of a subject, including administering to the subject an effective amount of pharmaceutically-acceptable nitrite, such as a salt thereof, so as to increase blood flow to a tissue of the subject. The blood flow may be specifically increased in tissues in regions of low oxygen tension. The present disclosure also provides a method for decreasing a subject's blood pressure, comprising administering to the subject an effective amount of pharmaceutically-acceptable nitrite so as to decrease the subject's blood pressure.

Problems solved by technology

Thus, in vivo studies have concluded that physiological levels of nitrites do not serve as a source for NO, and that physiological levels of nitrites do not have a role in regulating blood pressure.

These high concentrations of nitrite produce clinically significant methemoglobinemia, potentially decreasing oxygen delivery.

While these high concentrations of nitrite have been shown to decrease blood pressure in humans, the amount of methemoglobin formed precluded a use for nitrite in the treatment of other medical conditions.

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