Assessing the physiological concentration and targets of nitric oxide in brain tissue

Abstract

Low nanomolar concentrations of nitric oxide activate guanylyl cyclase to produce cGMP, which has diverse physiological effects. Higher concentrations inhibit mitochondrial respiration at cytochrome c oxidase and this has been proposed to be important physiologically, increasing oxygen permeation into tissue (by reducing the oxygen use of cells near blood vessels), activating AMP kinase, and regulating the relationship between cerebral blood flow and oxygen use. It is unclear, however, whether nitric oxide can accumulate physiologically to concentrations at which inhibition of respiration occurs. In rat cerebellar slices, we activated nitric oxide production from each isoform of nitric oxide synthase. Only activation of inducible nitric oxide synthase, which is expressed pathologically, caused any significant inhibition of respiration. Modelling oxygen and nitric oxide concentrations predicted that, in vivo, physiological nitric oxide levels are too low to affect respiration. Even pathologically, the nitric oxide concentration may only rise to 2.5 nm, producing a 1.5% inhibition of respiration. Thus, under physiological conditions, nitric oxide signals do not inhibit respiration but are well-tuned to the dynamic range of guanylyl cyclase activation.

Glial and neuronal control of brain blood flow

“…These in vivo values, which can be mimicked by superfusing brain slices with solution equilibrated with 20% O 2 (ref. 70), are comparable to or lower than the K m values for O 2 in the synthesis of 20-HETE and NO. Thus, at in vivo levels of O 2 , we expect NO and 20-HETE synthesis to be significantly limited by the amount of O 2 available.…”

The effect of nitric oxide on synaptic vesicle proton gradient and mitochondrial potential of brain nerve terminals

“…respiratory complex IV cyto chrome c oxidase, for binding sites of which nitric oxide competes with oxygen, is the most sensitive target of NO in mitochondria. Some scientists be lieve the inhibition of this enzyme is a manifestation of the pathological action of nitric oxide, since the inhibition occurs at NO concentrations more than a few tens of nanomole (nM/l), which are detected in vivo upon activation of the inducible form of NO synthase [12]. However, other scientists, noting the reversibility of the inactivation of cytochrome c oxidase by low (nanomolar) concentrations of nitric oxide, considered NO as a physiological regulator of mitochondrial respiration [32,33].…”

“…The high concentration of nitric oxide is also observed upon various neurodegenerative diseases, trauma or is chemia, which is accompanied by excitotoxicity. It is worth noting that the concentrations of nitric oxide up to 1 µM were formerly considered as physiologi експериментальні роботи doi: http://dx.doi.org/10.15407/ubj87.06.064 cal [10], but now this view is subject to revision [11], and NO concentrations even in the range of several tens of nanomoles are regarded as pathological [12].…”

Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function

“…To uncouple O 2 consumption and supply due to blood flow, we performed similar measurements of P tiss,O2 in acute pituitary slices where the GH cell network functionally responds to GHRH application (10), but in the presence of constant O 2 levels in the perfusate (24). In 200-μm GH-eGFP pituitary slices, GH cell network motifs spontaneously displayed much larger and longer downward O 2 deflections than those observed in living mice (P < 0.001, n = 7 slices).…”