Examination of Potential Mechanisms in the Enhancement of Cerebral Blood Flow by Hypoglycemia and Pharmacological Doses of Deoxyglucose

Horinaka, Naoaki; Artz, Nicole; Jehle, Jane; Takahashi, Shinichi; Kennedy, Charles; Sokoloff, Louis

doi:10.1097/00004647-199701000-00008

Cited by 35 publications

(31 citation statements)

References 34 publications

(7 reference statements)

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“…This is consistent with other reports showing bradycardia during either acute or chronic severe hypoglycemia in rats (Bryan and Pelligrino, 1988;Bryan et al, 1994). At the level of hypoglycemia (o2.0 mmol/L) achieved in our model, it is also assumed that there would be an abrupt increase in cerebral blood flow, as shown by other investigators (Bryan et al, 1994;Horinaka et al, 1997;Choi et al, 2001). Using nuclear magnetic resonance spectroscopy to measure brain glucose levels, the cerebral blood flow increase during hypoglycemia occurs at a plasma glucose threshold of 2.0 mmol/L, at which point the brain glucose concentration approaches zero (Choi et al, 2001).…”

Section: Discussionsupporting

confidence: 94%

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Tkacs

Pan

Raghupathi

et al. 2005

J Cereb Blood Flow Metab

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Intensive insulin therapy in patients with type 1 diabetes mellitus reduces long-term complications; however, intensive therapy is also associated with a three-fold increase in hypoglycemic episodes. The present study in conscious rats characterizes the physiologic and neuropathologic consequences of a single episode of moderate hypoglycemia. In this model, intravenous insulin is used to reduce plasma glucose to 30 to 35 mg/dL for 75 mins. This single hypoglycemic insult acutely induces hypoglycemia-associated autonomic failure (HAAF), with epinephrine responses to hypoglycemia reduced more than 36% from control. Neuropathology after this insult includes the appearance of dying cells, assessed with the marker Fluoro-jade B (FJ). After hypoglycemic insult, FJ þ cells were consistently seen in subdivisions of the medial prefrontal cortex, the orbital cortex, and the piriform cortex. There was a significant correlation between depth of hypoglycemia and number of FJ þ cells, suggesting that there is a critical threshold below which vulnerable cells begin to die. These data suggest that there is a population of cells that are vulnerable to moderate levels of hypoglycemia commonly experienced by patients with insulin-treated diabetes. These cells, which may be neurons, are primarily found in cortical regions implicated in visceral perception and autonomic control, raising the possibility that their loss contributes to clinically reported deficits in autonomic and perceptual responses to hypoglycemia.

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Section: Discussionsupporting

confidence: 94%

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Tkacs

Pan

Raghupathi

et al. 2005

J Cereb Blood Flow Metab

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“…Inhibition of cerebral glucose utilization by hypoglycemia or pharmacological doses of 2-deoxyglucose (2-DG) has been found to result in marked increases in CBF (3,10). Inasmuch as these conditions depress cerebral energy metabolism, the increases in CBF cannot be ascribed to vasodilator products of glucose and/or oxygen metabolism.…”

Section: G -Nitro-largininementioning

confidence: 99%

Regional differences in mechanisms of cerebral circulatory response to neuronal activation

Gotoh

Kuang

Nakao

et al. 2001

American Journal of Physiology-Heart and Circulatory Physiology

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. Regional differences in mechanisms of cerebral circulatory response to neuronal activation. Am J Physiol Heart Circ Physiol 280: H821-H829, 2001.-Vibrissal stimulation raises cerebral blood flow (CBF) in the ipsilateral spinal and principal sensory trigeminal nuclei and contralateral ventroposteromedial (VPM) thalamic nucleus and barrel cortex. To investigate possible roles of adenosine and nitric oxide (NO) in these increases, local CBF was determined during unilateral vibrissal stimulation in unanesthetized rats after adenosine receptor blockade with caffeine or NO synthase inhibition with N G -nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole (7-NI). Caffeine lowered baseline CBF in all structures but reduced the percent increase during stimulation only in the two trigeminal nuclei. L-NAME and 7-NI lowered baseline CBF but reduced the percent increase during stimulation only in the higher stations of this sensory pathway, i.e., L-NAME in the VPM nucleus and 7-NI in both the VPM nucleus and barrel cortex. Combinations of caffeine with 7-NI or L-NAME did not have additive effects, and none alone or in combination completely eliminated functional activation of CBF. These results suggest that caffeine-sensitive and NO-dependent mechanisms are involved but with different regional distributions, and neither fully accounts for the functional activation of CBF. adenosine; nitric oxide; caffeine; 7-nitroindazole; N G -nitro-Larginine NUMEROUS STUDIES HAVE ESTABLISHED that neuronal functional activation is associated with increases in both cerebral energy metabolism and blood flow (CBF) in components of the activated neural pathway (8,18,(30)(31)(32). The increases in energy metabolism evoked by functional activation have been shown to be proportional to the increases in spike frequency in the afferent inputs to the activated areas (13, 32) and to be due mainly to activation of Na ϩ -K ϩ -ATPase activity (21, 32). The mechanisms mediating the increases in CBF during functional activation remain, however, largely undefined. A popular hypothesis proposed by Roy and Sherrington (27) was that CBF is intrinsically regulated by products of energy metabolism to meet the altered metabolic demands associated with functional activity. This hypothesis received support from subsequent findings that CBF is raised by increased CO 2 tension, lowered pH, and decreased oxygen tension, all expected consequences of increased tissue metabolism, and reduced by changes in these chemical factors in the opposite direction, to be expected with decreased metabolism (14). Since then, many other endogenous agents that affect cerebral blood vessels, e.g., nitric oxide (NO), adenosine, adenine nucleotides, K ϩ , prostaglandins, vasoactive intestinal peptide, etc., have been identified and considered as possible candidates, but not one of them, alone or in combination with others, has yet been proven to account fully or even to be essential for the enhancement of CBF by neuronal activation.Inhibition of cerebral glucose utilization by hypo...

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“…For example, Powers et al (1996) interpreted the observation of no change in task-activated flow increases in hypoglycemia to be that blood flow is uncoupled with metabolism and neural activity in hypoglycemia. However, while such metabolism studies have provided variable results by methods of FDG PET (Horinaka et al, 1997;Wienhard, 2002), the methods of functional magnetic resonance (MR) imaging can provide an alternative approach. Therefore, in this study, we used high-field MR perfusion, R 2 0 and BOLD imaging to evaluate perfusion and oxidative metabolism in normal adult volunteers.…”

Section: Introductionmentioning

confidence: 99%

Human Cerebral Blood Flow and Metabolism in Acute Insulin-Induced Hypoglycemia

Kennan

Takahashi

Pan

et al. 2005

J Cereb Blood Flow Metab

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How the human brain functions under conditions of acute hypoglycemia remains a complex question by virtue of the potential simultaneous shifts in processes of perfusion, metabolism, and changing demand. We examined this issue by measuring cerebral blood flow (CBF) and oxidative metabolism (CMRO 2 ) in insulin-induced hypoglycemic (HG) and euglycemic (EG) conditions at rest and during motor activation in normal human subjects using magnetic resonance (MR). Experiments were performed on 12 subjects (9M, 3F). The protocol consisted of insulin-induced hypoglycemia (targeting a HG of 60 mg/dL) followed by euglycemia, or in reverse order, each phase lasting approximately 1.5 h. Euglycemia was performed with the same insulin infusion rate so as to match the hypoglycemic phase. Magnetic resonance data were acquired 30 mins after the target plasma glucose was achieved so as to minimize any acute effects. Although the depth of hypoglycemia achieved in the present study was relatively small, the present data found a significant increase in flow in motor cortex with mild hypoglycemia, from 56.4713.6 mL/100 g min (euglycemia) to 64.37 7.6 mL/100 g min (hypoglycemia). Using the Renkin-Crone exponential model of oxygen extraction with MR models of susceptibility-based relaxation, analysis of the flow measurements, relaxation and BOLD data also implied that throughout the studies, metabolism and flow remained coupled. Elementary motor task activation was not associated with any consistent larger activated flows. Thus it remains that although mild hypoglycemia induced an increase in basal flow and metabolism, a similar increase was not seen in task activation.

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Examination of Potential Mechanisms in the Enhancement of Cerebral Blood Flow by Hypoglycemia and Pharmacological Doses of Deoxyglucose

Cited by 35 publications

References 34 publications

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Cortical Fluoro-Jade Staining and Blunted Adrenomedullary Response to Hypoglycemia after Noncoma Hypoglycemia in Rats

Regional differences in mechanisms of cerebral circulatory response to neuronal activation

Human Cerebral Blood Flow and Metabolism in Acute Insulin-Induced Hypoglycemia

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