Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation

Abstract

. Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 291: H2026 -H2035, 2006. First published June 23, 2006 doi:10.1152/ajpheart.00407.2006.-Accumulating evidence suggests that the simple and ubiquitous anion salt, nitrite (NO 2 Ϫ ), is a physiological signaling molecule with potential roles in intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling, and cytoprotection after ischemia-reperfusion. Human and animal studies of nitrite treatment and NO gas inhalation provide evidence that nitrite mediates many of the systemic therapeutic effects of NO gas inhalation, including peripheral vasodilation and prevention of ischemia-reperfusion-mediated tissue infarction. With regard to nitritedependent hypoxic signaling, biochemical and physiological studies suggest that hemoglobin possesses an allosterically regulated nitrite reductase activity that reduces nitrite to NO along the physiological oxygen gradient, potentially contributing to hypoxic vasodilation. An expanded consideration of nitrite as a hypoxiadependent intrinsic signaling molecule has opened up a new field of research and therapeutic opportunities for diseases associated with regional hypoxia and vasoconstriction.hemoglobin; hypoxia; S-nitrosated albumin; cysteine 93 HYPOXIC VASODILATION is a conserved systemic physiological response that matches blood flow and oxygen delivery to tissue metabolic demand. This hypoxic response has been appreciated for more than 100 years since the initial description by Roy and Brown in 1879 (80). This response is thought to involve feedback mechanisms that require oxygen or pH sensing of a divergence in the normal relationship between delivered blood oxygen and tissue oxygen consumption (94). This leads to the feedback generation of putative vasodilatory effectors that increase blood flow to maintain adequate tissue oxygenation. Important to the considerations of the mechanisms responsible for oxygen sensing, in mammals hypoxic vasodilation appears to occur as the hemoglobin desaturates from 60% to 40%, around a partial pressure of oxygen ranging from . Surprisingly, measurements of microcirculatory and tissue oxygen tension and hemoglobin oxygen saturation using modern methodologies suggest that much of the oxygen delivery occurs within the resistance arterioles, especially in the case of skeletal muscle (91). Thus, in these microvascular beds, the anatomical site of hypoxic sensing is proximal to the site of resistive control (arterioles and arteriolar capillaries). In other tissues, such as heart and brain, more oxygen is extracted within the capillary network. This creates a paradox as to how hypoxic sensing can modulate retrograde feedback vasodilation in these tissues. The solution to this paradox has been in part solved by the work of , who suggested that acetycholine-dependent vasodilation of the capillary or venous circulation produces retrograde intracellular propagation of ...

Plasma methemoglobin as a potential biomarker of anemic stress in humans

“…The proposed mechanism for increased MetHb may include NO-mediated Hb oxidation or reduction of nitrite (NO 2 -) by DeoxyHb, as suggested by experimental and clinical studies. 3,[18][19][20][21][22] It will be important to assess these changes in subsequent studies to determine if the increase in MetHb is reflective of activated adaptive mechanisms (nNOS) 7 and/ or increased OxyHb desaturation to DeoxyHb and tissue hypoxia [18][19][20][21][22] during acute hemodilutional anemia.…”

“…HO -. [18][19][20][21][22] In either case, MetHb may be a biomarker of increased NO production and/or decreased oxygen saturation in local vascular beds. These proposed mechanisms may be particularly favoured during anemia since local production of NO would be supported by an increase in tissue oxyHb extraction which is known to occur in anemic vascular beds.…”

“…All data are presented as mean and significance was assigned at P \ 0.05. Results A significant decrease in Hb [118 (20) . Regression analysis revealed a significant relationship between the change in Hb and MetHb (F = 40.3; P \ 0.001) but not between the change in Hb and CarboxyHb (F = 0.2; P = 0.694).…”

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…For example, the oral administration of S-nitroso-N-acetylcysteine prevented the onset of NAFLD in response to a methionine-choline deficient diet [110,111]; however, it is unclear whether the benefit was due to NO or Nacetylcysteine exposure. Recently, inhaled NO administration was shown to accelerate the restoration of liver function in transplantation patients presumably through increased circulating levels of nitrite [112], a newly recognized vascular endocrine transporter of NO [113] that protects against heart and liver ischemia-reperfusion injury [114]. In models of chronic alcohol consumption eNOS activity is decreased in liver through increased expression of the inhibitory protein caveolin-1 and/or decreased eNOS phosphorylation [115,116].…”

Low Nasal NO in Congenital Heart Disease With Systemic Right Ventricle and Postcardiac Transplantation

“…Because NO is an important mediator of coronary microcirculatory function,9 and its bioavailability may be crucial to the development of heart failure,10, 11 this suggests NO measurements may have clinical utility as a biomarker for assessing heart failure risks. However, NO measurement in blood is difficult because of NO's extremely short half‐life (<2 ms) 12. Given NO is also continuously produced by the airway epithelium,13, 14 this suggests the possibility that nasal NO (nNO) measurements, easily obtained noninvasively via the nares,15 might be suitable as a proxy for blood NO.…”