NADH augments blood flow in physiologically activated retina and visual cortex

Abstract

The mechanism(s) that increase retinal and visual cortex blood flows in response to visual stimulation are poorly understood. We tested the hypothesis that increased transfer of electrons and protons from glucose to cytosolic free NAD ؉ , reducing it to NADH, evoked by increased energy metabolism, fuels redox-signaling pathways that augment flow. The near-equilibrium between free cytosolic NADH͞NAD ؉ and lactate͞pyruvate ratios established by lactate dehydrogenase predicts that transfer of additional electrons and protons from injected lactate to NAD ؉ will augment the elevated blood flows in stimulated retina and cortex, whereas transfer of electrons and protons from NADH to injected pyruvate will attenuate the elevated flows. These predictions were tested and confirmed in rats. Increased flows evoked by stimulation also were prevented by inhibition of nitric oxide synthase. These findings support an important role for cytosolic free NADH in fueling a signaling cascade that increases • NO production, which augments blood flow in photostimulated retina and visual cortex. P hysiological work, ranging from muscle contraction to neural activity in the brain and phototransduction in the retina, increases energy metabolism and blood flow (1-5). The increase in energy metabolism is explained by increased synthesis of ATP to fuel the work performed. However, the metabolic basis for the increase in blood flow remains enigmatic. Until recently it was widely believed that the increased flow was needed to provide more oxygen and glucose to support increased energy metabolism and to remove the products of energy metabolism that inhibit ATP synthesis. However, increased brain blood flow and glucose utilization evoked by neural activity exceed increased oxygen consumption by as much as 10-fold despite normal or elevated oxygen levels (2, 3). And, enhanced flow is not needed to augment glucose uptake for brief periods of neural activity (6-8).Observations in rats support the hypothesis that electrons and protons (E&P) carried by free cytosolic NAD (NAD c ) mediate increased blood flows in contracting skeletal muscle and in stimulated whisker barrel cerebral cortex (1); varying the rates of transfer of E&P to and from free NAD c evokes corresponding changes in flow. NAD is the major carrier of E&P from fuels for synthesis of ATP (9). When glucose is the fuel, E&P must be transferred to free NAD c ϩ , reducing it to NADH c , before ATP synthesis. ATP is then synthesized in the cytosol by substrate phosphorylation followed by production of pyruvate that is oxidized in mitochondria for ATP synthesis by oxidative phosphorylation. E&P carried by NADH c also are transferred to mitochondrial NAD (NAD m ϩ ) via electron shuttles and fuel ATP synthesis by oxidative phosphorylation.The presence of lactate in resting tissues indicates that E&P are transferred to free NAD c ϩ and pyruvate is produced by glycolysis faster than they are used for ATP synthesis by means of oxidative phosphorylation; lactate dehydrogenase (LDH) reoxidizes ''exc...

Interactions Between Hyperglycemia and Hypoxia

“…This conclusion and recent observations that increased retinal and visual cortex blood flows evoked by photostimulation are mediated by an increase in NADHcϰL/P (53,54) are consistent with the central role of free NADc in fueling energy metabolism and signaling pathways that coordinate blood flow with energy metabolism in resting cells, during physiological work, and in pathophysiological states including diabetes and hypoxia.…”

Effects of lactate on the early visual cortex of non-human primates, investigated by pharmaco-MRI and neurochemical analysis

“…We must consider two possible reasons for the lack of CBF changes. The first reason is most likely the very low changes in CBF induced by our lactate application protocol, which would agree with the findings in rats described by Ido et al (2004). The second reason is related to the detection threshold of the FAIR recordings, which is just within the range of the expected CBF changes (namely, approximately 5%).…”

“…However, these vascular effects were triggered by relatively high doses of lactate. Therefore, we only expected subtle changes in CBF using our infusion protocol, which is comparable to a protocol used by Ido et al that produced CBF changes only in the range of 4% (Ido et al, 2004). Fig.…”

“…For example, a bolus injection that increases systemic lactate to 9.8 ± 2.4 mM has induced a change in CBF in the range of 38-53% in human visual cortex (Mintun et al, 2004). This finding contrasts with the results of a subtle and continuous application of lactate (2 mmol/kg) in rats (reaching plasma concentrations of 3.5 ± 0.4 mM), which did not yield CBF changes greater than 4% (Ido et al, 2004). We verified the CBF changes induced by lactate application (low-dose and continuous infusion) using FAIR recordings, which did not demonstrate reliable CBF changes.…”

“…Although lactate-induced increases in neuronal activity have been described in rat hippocampus, the reason for these increases is yet not fully understood (Bergold et al, 2009). Furthermore, lactate is known to increase CBF by inducing the production of nitric oxide and other vasodilatory molecules (Ido et al, 2004;Gordon et al, 2008). However these CBF changes apparently depend to a certain degree on lactate dose and application modality (bolus vs. slow infusion).…”