Regulation Of rCBF Research Articles

Inhibition of aquaporin-4 significantly increases regional cerebral blood flow

The effects of the aquaporin-4 (AQP-4) inhibitor TGN-020 on regional cerebral blood flow (rCBF) was examined in wild-type (WT) and AQP-4 knockout (KO) mice in vivo. Although baseline absolute rCBF of WT and KO mice were equivalent (158.9 ± 17.7 and 155.5 ± 10.4 ml/100 g/min, respectively), TGN-020 produced a significant increase in rCBF compared with saline-treated WT mice (control), reaching a plateau 20 min after administration (118.45 ± 8.13%, P<0.01). TGN-020 showed no effect on KO mice, supporting the concept that the observed increase in rCBF in WT mice was AQP-4 dependent. Administration of acetazolamide (positive control) produced an even greater increase in rCBF in WT compared with TGN-020 and a similar response in KO mice as well, reaching a sustained plateau 5 min after administration (138.50 ± 9.75 and 138.52 ± 9.76%, respectively, P<0.01 compared with baseline or saline-treated control mice). The study demonstrated that AQP-4 plays a role in regulation of rCBF.

Cerebral Blood Flow Response to Functional Activation

Cerebral blood flow (CBF) and cerebral metabolic rate are normally coupled, that is an increase in metabolic demand will lead to an increase in flow. However, during functional activation, CBF and glucose metabolism remain coupled as they increase in proportion, whereas oxygen metabolism only increases to a minor degree-the so-called uncoupling of CBF and oxidative metabolism. Several studies have dealt with these issues, and theories have been forwarded regarding the underlying mechanisms. Some reports have speculated about the existence of a potentially deficient oxygen supply to the tissue most distant from the capillaries, whereas other studies point to a shift toward a higher degree of non-oxidative glucose consumption during activation. In this review, we argue that the key mechanism responsible for the regional CBF (rCBF) increase during functional activation is a tight coupling between rCBF and glucose metabolism. We assert that uncoupling of rCBF and oxidative metabolism is a consequence of a less pronounced increase in oxygen consumption. On the basis of earlier studies, we take into consideration the functional recruitment of capillaries and attempt to accommodate the cerebral tissue's increased demand for glucose supply during neural activation with recent evidence supporting a key function for astrocytes in rCBF regulation.

Allosteric release of nitric oxide from hemoglobin does not mediate neurovascular coupling

Neuronal activation leads to an increase in regional cerebral blood flow (rCBF) and blood oxygenation (rCBO). The underlying mechanisms of neurovascular coupling are poorly understood. Recently a new model of activity induced vascular regulation was proposed by Stamler et al. (1997) based on the fact that nitric oxide (NO), a potent vasodilator, binds to hemoglobin in the oxygenated state (oxy-Hb) but is released upon deoxygenation of hemoglobin (deoxy-Hb). It was suggested that during cellular activity oxygen consumption locally increases which causes deoxygenation of hemoglobin and release of NO. Indeed it has recently been shown that red blood cell-bound NO mediates hypoxic vasodilation in vitro, and transpulmonary gradients of hemoglobin-bound NO are evident in patients with congestive heart failure (Datta et al., 2004). According to this elegant model of combined oxygen and NO release, blood flow will be directly matched to tissue oxygen demands. To test this model as a physiological mechanism of neurovascular coupling in the brain, we measured rCBF and rCBO responses to functional activation under hyperbaric oxygenation (3 ATA, FiO2 1.0) in the anesthetized rat. During hyperbaric oxygenation oxygen supply to tissue is entirely provided through physically dissolved oxygen. During activation no deoxygenation of hemoglobin and thus no allosteric release of NO occurs. Laser Doppler flowmetry combined with microfiber Hb-spectroscopy was performed through the thinned skull in rats to measure relative changes in rCBF and rCBO and cortical hemoglobin saturation. Averaged rCBF and rCBO responses to electrical forepaw stimulation (3 Hz, 10 s stimulation period) were recorded under normobaric normoxia and compared with responses during hyperbaric hyperoxygenation. Hyperbaric hyperoxygenation increased hemoglobin saturation within the microcirculation from 44 2 to 103 3%. The deoxy-Hb decrease normally occurring during functional activation disappeared. The oxy-Hb increase was unchanged, and the rCBF response to functional activation was increased but not decreased under hyperbaric hyperoxygenation compared with control responses. In most animals the observed increase in the rCBF response was paralleled by an increase in the amplitude of somatosensory evoked potentials. Our results suggest that in contrast to the in-vitro situation and to pathophysiological conditions of severe hypoxia rCBF regulation during physiological neuronal activation involves other mechanisms than oxygen-dependent delivery and release of NO from hemoglobin.

脳血流の神経性調節をめぐって

Local metabolites have long been considered to play an important physiological role in regulating regional cerebral blood flow (rCBF). However, the evidence reviewed here emphasizes that the regulation of rCBF by central cholinergic nerves is independent of regional metabolism. Activation of the intra cranial cholinergic fibers originating in the nucleus basalis of Meynert (NBM) and septal complex releases acetylcholine in the cortex and hippocampus, which results in vasodilation and an increase in rCBF in the cortex and hippocampus via activation of both muscarinic and nicotinic acetylcholine receptors. Cutaneous sensory stimulation activates the cholinergic nerves originating from the NBM to enhance rCBF. The increase in rCBF at the defuse cortices during walking appears to include an excitation of this NBM-originating cholinergic vasodilation system. Other various inputs to the NBM may have a similar effects to enhance rCBF via activation of that cholinergic system, provided the stimulation is delivered properly. Thus the combination of pharmacological and nonpharmacological techniques may provide a balance in our attempts to improve cholinergic replacement therapy.

Cerebrocortical and medullary blood flow changes after general opiate receptor blockade during hemorrhagic shock in cats.

The effect of centrally induced opiate receptor blockade on regional cerebral blood flow (rCBF) was studied in anesthetized, ventilated cats during the course of hemorrhagic shock. The blood flow of the medulla and the parietal cortex was measured with the H2-gas clearance technique. Hemorrhagic shock was produced by lowering the systemic mean arterial pressure to 60 mmHg for 120 min by blood withdrawal. Central opiate receptor blockade was induced by 10 micrograms/kg intracerebroventricularly (i.c.v.) injected naloxone at the 60th min of the bleeding period. Cortical blood flow showed no improvement after i.c.v. naloxone administration. Medullary blood flow, however, increased significantly and approached the pre-bleeding control flow values following central opiate receptor blockade. The results indicate involvement of endogenous opioid mechanisms in the regulation of rCBF during hemorrhage and may provide an explanation for the previously described beneficial effects of naloxone in hemorrhagic shock.

Regulation of rCBF by diffusible signals: An analysis of constraints on diffusion and elimination

AbstractLocal changes in cerebral hemodynamics are observed within a few hundred milliseconds of changes in neural activity. If hemodynamic responses are mediated by passive diffusion of a spatial signal (from the site of neural activity to the microvessels) then the dynamics of the response suggest a lower limit on the signal's apparent diffusion and elimination. The aim of this work was to estimate these limits and narrow the field of possible candidate substances.A simple biophysical simulation was used to examine how the time course of concentration changes in a spatial signal, at the site of action (microvessels), depends on key diffusion parameters (source geometry, apparent diffusion and elimination half‐life). The simulations suggested (1) that the rise in signal concentration is mostly a function of source geometry and diffusion. Conversely falls in concentration depend on elimination and (2) even when sources are very sparsely distributed Nitric Oxide would have a sufficiently fast diffusion and elimination to signal the early components of activity‐dependent hemodynamic response by passive diffusion. © 1995 Wiley‐Liss, Inc.

Neural regulation of cerebral blood flow

The brain is encased in a rigid container, the skull, and thus the total volume of cerebral blood flow (CBF) per se is maintained at a stable level within very narrow ranges. The change in regional CBF (rCBF) has been considered to be broadly attributable to the rate of glucose metabolism by regional neurons. Although autonomic nerves have been proposed to contribute to maintenance of autoregulation of the CBF, the regulation of rCBF by metabolites produced in the regional cerebral tissues has received more attention. However, the fact that most blood vessels in the brain are innervated by fibers containing noradrenaline, acetylcholine, serotonin and some peptides, indicates a functional role for these neurons in the regulation of rCBF. Recently, Alzheimer's disease has become an important research target at both the clinical and neuroscientific levels. In this disease, degeneration of cells in the basal forebrain, e.g., cholinergic neurons originating in the nucleus basalis of Meynert (NBM) and projecting to the cerebral cortex, is quite striking. However, the function of these cholinergic neurons in the cerebral cortex has remained unclear until recently. Over the last few years, new evidence concerning the role of cortical and hippocampal cholinergic fibers has accumulated and revealed a physiological vasodilative function for these cholinergic fibers. I would like to introduce recent studies on vasodilative regulation of the cerebral cortex and hippocampus by these central cholinergic nerves originating in the NBM and septal complex. I shall also briefly introduce the related subjects of vasomotor regulation in the brain by other central noradrenergic, serotonergic, and dopaminergic fibers, and also by peripheral sympathetic and parasympathetic nerves.

Chronic parasympathetic sectioning decreases regional cerebral blood flow during hemorrhagic hypotension and increases infarct size after middle cerebral artery occlusion in spontaneously hypertensive rats.

Regional cerebral blood flow (rCBF) during controlled hemorrhagic hypotension (140-20 mm Hg) was assessed 10-14 days after chronic unilateral sectioning of parasympathetic and/or sensory fibers innervating pial vessels in spontaneously hypertensive rats (SHR). rCBF was measured in the cortical barrel fields bilaterally by laser Doppler blood flowmetry. Immunohistochemistry of middle cerebral artery (MCA) whole mount preparations was used to verify the surgical lesion. During hemorrhagic hypotension, rCBF was equivalent on the two sides in shams, after selective sensory denervation, or in parasympathetically sectioned animals exhibiting small decreases (less than or equal to 30%) in immunoreactive vasoactive intestinal peptide (VIP)-containing fibers. After chronic parasympathetic denervation, decreases in perfusion pressure were accompanied by greater reductions in rCBF on the lesioned side; changes in vascular resistance were also attenuated on that side. The rCBF response to hypercapnia (PaCO2 50 mm Hg), however, was symmetrical and robust. To examine the effects of impaired neurogenic vasodilation on the pathophysiology of cerebral ischemia, infarct size was measured 24 h following tandem MCA occlusion in denervated animals. Infarction volume was larger after selective parasympathetic sectioning (sham, 156 +/- 27 vs. 196 +/- 32 mm3, respectively) but only in those denervated animals demonstrating greater than or equal to 40% decrease in immunoreactive VIP-containing fibers within the ipsilateral MCA. Lower than expected blood flow/perfusion pressure in the cortex distal to an occluded blood vessel may relate the observed blood flow responses to the occurrence of larger cortical infarcts in parasympathetically denervated animals. If true, the findings suggest a novel role for neurogenic vasodilation in the pathophysiology of cerebral ischemia and in rCBF regulation within the periinfarction zone.

Effect of Intracisternal Injection of Endothelin-1 on Regional Cerebral Blood Flow in Cats

The effect of endothelin-1 on regional cerebral blood flow (rCBF) was investigated in adult mongrel cats. Endothelin-1 was injected into the cisterna magna and rCBF was measured by the hydrogen clearance method before and every 30 minutes for 180 minutes after the injection. Endothelin-1 (10(-11) mol and 10(-9) mol) induced a significant decrease in rCBF and an increase in arterial pressure. The effects of endothelin-1 on rCBF and arterial pressure were mediated, at least in part, by Ca2+, because pretreatment with intracisternally injected nicardipine prevented the changes. Cerebral angiograms obtained before and after endothelin-1 injection demonstrated severe constriction of the basilar artery, but constriction of the internal carotid and middle cerebral arteries was mild. Since the rCBF measured was in the territory of the middle cerebral artery, the decrease in blood flow was probably not solely due to the artery constriction. Other mechanisms such as arteriole constriction and/or regulation of rCBF by the central nervous system may also occur.

Regulation of rCBF by intracortical vasoactive intestinal polypeptide-containing neurons. Immunohistochemical and hydrogen clearance study in rats.

The role of intracortical vasoactive intestinal polypeptide (VIP)-containing neurons in the regulation of cortical blood flow was investigated in rats by immunohistochemical and hydrogen clearance methods. Immunohistochemical studies revealed an intimate association between intracortical VIP-containing neurons and small blood vessels. Intracortical injection of a VIP solution (10(-5) M) produced significantly higher blood flow in the treated cortex (mean +/- standard error of the mean: 46.2 +/- 4.0 ml/100 gm/min) than in the untreated cortex (36.9 +/- 2.4 ml/100 gm/min). These data suggest that intracortical VIP-containing neurons produce dilatation of intracortical blood vessels.

1363 PGE1 AND NEONATAL CEREBRAL BLOOD FLOW

Alterations in regional cerebral blood flow (rCBF) may be critical in the genesis of intra-ventricular hemorrhage and hypoxicischemia encephalopathy. rCBF regulation is mediated via several factors including prostaglandins (PG). The effect of PGE1, the most commonly used PG in the newborn period, on rCBF was evaluated in 6 piglets, 1-3 d.o. Aorta, inferior vena cava, left ventricle and sagittal vein were catheterized to monitor blood gas, glucose and pressure. PGE1 was administered in the left internal carotid artery in successive increasing doses of 10−7, 10−6, and 10−5 g/kg/bolus q 20 mins, to awake piglets. rCBF was measured by radiolabelled microspheres (141Ce, 46Sr, 85Nb, 95Sc) 45 sec post bolus.PGE1 doses of 10−7 g/kg produced a 40% decrease in rCBF.In contrast, no effect was observed at higher doses. Blood pressure and gases remained constant during the study. There was no correlation between blood pressure and rCBF at all doses of PGE1. However, there was a positive correlation between cerebral resistance rCBF only at the dose of 10−7 g/kg PGE1. This implies that physiological concentration of PGE1 (10−7 g/kg) as found in adult cerebral vessels, may contribute to neonatal rCBF autoregulation.