Regulation Of Cortical Blood Flow Research Articles

Functional magnetic resonance imaging responses in CADASIL

ObjectivesThe magnitude of the blood oxygen dependent level (BOLD) functional MRI (fMRI) response to visual stimulation is reduced in the small vessel disease cerebral amyloid angiopathy (CAA), reflecting impaired vascular reactivity. We determined whether BOLD responses were reduced in another small vessel disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). MethodsBOLD fMRI data were collected using a visual stimulus (contrast-reversing checkerboard) and motor task (finger-tapping). The amplitude of BOLD responses in the visual cortex (visual stimulus) and motor cortex (motor task) were compared between 5 CADASIL, 18 CAA and 18 control subjects, controlling for age and hypertension. ResultsBOLD response varied by group for the visual stimulus (p<0.001) but not the motor task (p=0.47). After adjusting for age and hypertension, the estimated mean visual cortex BOLD amplitude response was 3.95% in CADASIL (95% confidence interval, CI 3.15–4.75%), 1.73% in CAA (95% CI 1.19–2.27%), and 2.88% (95% CI 2.39–3.37%) in controls. In CADASIL, the visual BOLD response was greater than in CAA (p<0.001) and controls (p=0.04). ConclusionsWe observed increased and unchanged BOLD amplitude responses in the visual and motor cortices of CADASIL patients, respectively. This suggests that cortical blood flow regulation by neuronal activity may be relatively preserved in CADASIL, in contrast to CAA where occipital vascular reactivity is impaired. Cortical vascular reactivity in CADASIL may be preserved because the disease-related injury is primarily subcortical, whereas increased activation may reflect compensatory mechanisms for subcortical injury.

Cellular transport of l-arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity.

Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of l-arginine is rate limiting for nitric oxide production and that plasma l-arginine concentration is decreased in diabetes. We therefore investigated whether regional renal blood flow regulation is affected by cellular l-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital, and the left kidney was exposed. Total, cortical, and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either l-homoarginine to inhibit cellular uptake of l-arginine or Nω-nitro- l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase. l-Homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. l-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both l-homoarginine and l-NAME were more pronounced in the control groups compared with the diabetic groups. Isolated cortical tubular cells displayed similar l-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased l-arginine uptake capacity. Diabetics had reduced l-arginine concentrations in plasma and medullary tissue but increased l-arginine concentration in cortical tissue. In conclusion, the reduced l-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular l-arginine and the upregulated cortical tissue l-arginine may protect cortical hemodynamics in diabetes.

Abstract T P407: Functional MRI-measured Vascular Reactivity is Preserved in CADASIL, but not Cerebral Amyloid Angiopathy

Objectives: Previous studies have demonstrated that the magnitude of the blood oxygen dependent level (BOLD) functional MRI (fMRI) response to visual stimulation is reduced in cerebral amyloid angiopathy (CAA) relative to controls, reflecting impaired vascular reactivity. We wished to determine if BOLD responses were reduced in an associated small vessel disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods: BOLD fMRI data were collected using a visual stimulus (contrast-reversing checkerboard) and motor task (finger-tapping). BOLD responses in the visual cortex (visual stimulus) and motor cortex (motor task) were compared between 5 CADASIL (55.0 ±12.9 years; 3 females), 18 CAA (72.1 ± 7.2 years; 6 females) and 22 control subjects (67.0 ±10.0 years; 9 females). One-way analysis of variance and multivariable-adjusted generalized models, controlling for age and hypertension, were used to compare groups with Tukey-Kramer’s correction for multiple comparisons. Results: BOLD response varied by group for the visual stimulus (p&lt;0.001) but not the motor task (p=0.48). After adjusting for age and hypertension, the estimated mean visual cortex BOLD response was 3.91% in CADASIL (95% confidence interval, CI, 3.12-4.70%), 1.71% in CAA (95% CI 1.23-2.20%), and 2.84% (95% CI 2.44-3.24%) in controls. In CADASIL, the BOLD response was greater than in CAA (p&lt;0.001) and controls (p=0.04). In CAA, the BOLD response was less than controls (p=0.009). No significant differences were observed for the motor task (p=0.51). Conclusions: We observed increased and unchanged BOLD responses in the visual and motor cortices of CADASIL patients, respectively. This suggests that cortical blood flow regulation by neuronal activity may be relatively preserved in CADASIL, in contrast to CAA where occipital vascular reactivity is impaired. Preserved reactivity in CADASIL may be because damage is primarily subcortical, whereas increased activation may reflect compensatory mechanisms for subcortical damage.

The Functional Role of Astrocyte Calcium Signaling in Cortical Blood Flow Regulation

Blood vessels in the CNS dilate in response to neuronal activity, thus supplying active neurons with adequate energy in a phenomenon called functional hyperemia. The cellular mechanism underlying functional hyperemia, known as neurovascular coupling, becomes dysfunctional in many disease states,

Brain and peripheral angiotensin II type 1 receptors mediate renal vasoconstrictor and blood pressure responses to angiotensin IV in the rat

Angiotensin (Ang) IV was reported to increase renal cortical blood flow (CBF) via putative angiotensin IV receptor (AT4) stimulation but reduce total renal blood flow (RBF) via angiotensin II type 1 (AT1) receptors. We investigated the effect of Ang IV on simultaneously measured mean arterial pressure (MAP), RBF, and CBF. The possible involvement of AT1 or AT4 receptors, the possible natriuretic effect, and responses to central administration were also explored. Intravenous injections of Ang IV dose dependently increased MAP and decreased CBF and RBF; these effects were abolished by AT1 receptor blockade. These reductions in CBF and RBF highly correlated as did renal vascular responses to Ang II and fenoldopam. Ang IV did not induce renal vasodilation even following AT1 receptor blockade. Intrarenal Ang IV infusion reduced CBF and RBF but had no natriuretic effect. Central Ang IV administration induced an AT1-mediated immediate increase in MAP and renal vascular resistance and a secondary increase in RBF. AT4 selective ligands, LVV-hemorphin-7 and AT4-16 (intravenous, intrarenal or intracerebroventricular), had no effects on MAP, RBF or urinary sodium excretion. Additional in-vitro experiments indicated that the majority of the Ang IV-sensitive aminopeptidase activity in kidney membranes is attributed to aminopeptidase-N. Insulin-regulated aminopeptidase (IRAP)/AT4 receptors are involved in neither the regulation of RBF or CBF nor in the handling of renal sodium. Ang IV increases MAP and induces renal vasoconstriction via stimulation of brain and peripheral AT1 receptors and may be involved in the regulation of renal blood flow and blood pressure.

Differential distribution of NADPH-diaphorase histochemistry in human cerebral cortex

β−Nicotinamidedinucleotide phosphate diaphorase (NADPH-d) colocalizes with NOS in the central nervous system. Two types of NADPH-d-positive neurons are present in the primate cerebral cortex: type 1, intensely and Golgi-like labeled neurons, a subset of GABAergic interneurons; type 2, lightly labeled neurons (divided into two subclasses, a first one having a lightly stained cell body bearing only one short process, and a second one showing intense NADPH-d staining with short processes extending radially). We have analyzed the distribution of NADPH-d activity in human frontal, temporal, and occipital cortical areas, finding remarkable laminar and interareal differences in cell size and distribution of the different cell types. There was a clear bias for type 1 neurons in infragranular layers in all areas considered; both in supra- and infragranular layers, their density was highest in frontal, and lowest in temporal cortex. The density of type 2 neurons was lower supragranularly in temporal cortex and infragranularly in occipital cortex. The overall density of type 2 cells was remarkably higher in occipital cortex than in the temporal and frontal ones. Type 1 neurons were significantly larger than type 2, and were smaller in the supragranular than in the infragranular subzone in occipital and temporal cortex. Type 1 cells were significantly larger in frontal cortex than in occipital and temporal cortex, and type 2 cells were significantly smaller in occipital than in temporal and frontal cortex. These area-related differences might reflect differences between heterotypic and homotypic cortex in the regulation of cortical blood flow.

State-dependent regulation of cortical blood flow and respiration in hamsters: response to hypercapnia during arousal from hibernation

State-dependent regulation of cortical blood flow and respiration in hamsters: response to hypercapnia during arousal from hibernation

State-dependent regulation of cortical blood flow and respiration in hamsters: response to hypercapnia during arousal from hibernation.

Hibernation is characterised by a global reduction of metabolism, body temperature and blood flow, while arousal from hibernation is achieved by the reversal of these processes. Our experiments were performed on Syrian hamsters that had been chronically implanted with a cortical thermocouple and an optical fibre over the contralateral cortex, and acutely implanted with thermocouples in the rectal, cheek pouch and interscapular brown adipose tissue (BAT). Measurements revealed large thermal gradients in the body of the arousing animals. Maximum whole-body metabolic rate, which was 2.4 times normal cenothermic resting metabolic rate, coincided not with rectal temperature but more closely with respiratory rate (RR) or BAT temperature. Regional cortical blood flow (rCBF), as measured by laser-Doppler flowmetry, changed in parallel with whole-body metabolic rate, peaking at 3.8 times the normal cenothermic resting levels, when rectal temperature was 15 degrees C. When BAT temperature was less than 25 degrees C, RR, rCBF and heart rate (HR) were decreased by breathing hypercapnic gas, but these parameters were unresponsive to hyperoxic gases. At cenothermia the RR and rCBF of anaesthetised hamsters was increased by exposure to hypercapnic gases. Exposure to hyperoxic gas decreased RR but had no effect on rCBF. The mechanisms regulating rCBF, HR and RR exhibit state-dependent sensitivities to hypercapnic and hyperoxic stimuli. The large increase in rCBF observed during arousal implies that cerebral autoregulation is temporarily suspended and suggests that hamsters effectively use endogenous mechanisms to minimise the pathology normally associated with dramatic increases in rCBF.

Basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS neurons in the rat neocortex: cellular basis for cortical blood flow regulation.

Stimulation of basal forebrain neurons results in local increases in cortical cerebral blood flow that are dependent upon cholinergic and nitrergic mechanisms. In the present study, we investigated the possibility that basal forebrain nitric oxide synthase (NOS)-containing neurons project to microvessels and NOS interneurons in the rat cerebral cortex. We performed quisqualic (QUIS) acid lesions of the basal forebrain and evaluated their effects on cortical NOS immunostained nerve terminals, with emphasis on those associated with microvessels and NOS interneurons, both at the light and/or electron microscopic levels. The results show that basal forebrain NOS neurons provide about one third of the overall cortical NOS innervation. Further, the data indicate that basalocortical NOS fibres establish privileged associations with microvessels and NOS neurons, as respective denervations of 60 and 45% were observed following lesion. At the electron microscopic level, most perivascular NOS neuronal elements corresponded to nerve terminals and a majority ( approximately 25%) of these were located in the immediate vicinity of the blood vessels, similar to the perivascular distribution reported previously for classic neurotransmitters/neuromediators. NOS terminals abutting on cortical NOS neurons were primarily nonjunctional. Altogether, these results raise the possibility that not only cholinergic but also nitrergic basal forebrain neurons are involved in the flow response observed following stimulation of the basal forebrain. Further, they suggest interactions between basalocortical and intracortical NOS neurons. We conclude that these interactions are involved in the spatial and temporal regulation of cortical perfusion following basal forebrain activation, and that they may become dysfunctional in pathologies such as Alzheimer's disease which affects both the basal forebrain and the cortical NOS neurons.

Selective Excitation of Subtypes of Neocortical Interneurons by Nicotinic Receptors

The cellular mechanisms by which neuronal nicotinic cholinergic receptors influence many aspects of physiology and pathology in the neocortex remain primarily unknown. Whole-cell recordings and single-cell reverse transcription (RT)-PCR were combined to analyze the effect of nicotinic receptor agonists on different types of neurons in acute slices of rat neocortex. Nicotinic receptor agonists had no effect on pyramidal neurons and on most types of interneurons, including parvalbumin-expressing fast spiking interneurons and somatostatin-expressing interneurons, but selectively excited a subpopulation of interneurons coexpressing the neuropeptides vasoactive intestinal peptide (VIP) and cholecystokinin. This excitation persisted in the presence of glutamate, GABA, and muscarinic receptor antagonists and in the presence of tetrodotoxin and low extracellular calcium, suggesting that the depolarization was mediated through the direct activation of postsynaptic nicotinic receptors. The responses were blocked by the nicotinic receptor antagonists dihydro-beta-erythroidine and mecamylamine and persisted in the presence of the alpha7 selective nicotinic receptor antagonist methyllycaconitine, suggesting that the involved nicotinic receptors lacked the alpha7 subunit. Single-cell RT-PCR analysis indicated that the majority of the interneurons that responded to nicotinic stimulation coexpressed the alpha4, alpha5, and beta2 nicotinic receptor subunits. Therefore, these results provide a role for non-alpha7 nicotinic receptors in the selective excitation of a subpopulation of neocortical interneurons. Because the neocortical interneurons expressing VIP have been proposed previously to regulate regional cortical blood flow and metabolism, these results also provide a cellular basis for the neuronal regulation of cortical blood flow mediated by acetylcholine.

Competitive inhibition of nitric oxide synthase prevents the cortical hyperemia associated with peripheral nerve stimulation.

With combined microdialysis and hydrogen clearance techniques for simultaneous local delivery of drugs and blood-flow measurement in the rat hindlimb sensory-motor cortex, we examined the role of nitric oxide in cerebral blood-flow regulation during sciatic nerve stimulation. Infusion of 1 mM nitric oxide synthase antagonist, N eta-nitro-L-arginine methyl ester (L-NAME), blocked the cortical blood-flow response to sciatic nerve stimulation (152 +/- 43 ml.min-1.100 g-1 of tissue in controls and 73 +/- 11 ml.min-1.100 g-1 in the presence of L-NAME; P less than 0.05). Addition of 10 mM L-arginine to the dialysate containing L-NAME partially restored the hyperemic response to nerve stimulation (125 ml.min-1.100 g-1). L-NAME also produced a decrease in baseline cerebral blood flow when compared with the control (66 +/- 14 ml.min-1.100 g-1 vs. 93 +/- 25 ml.min-1.100 g-1). We conclude that nitric oxide from activated neurons participates in the local regulation of cortical blood flow in response to sciatic nerve stimulation and also in the maintenance of basal cortical blood flow.

Regulation of cortical blood flow by the dorsal raphe nucleus: topographic organization of cerebrovascular regulatory regions.

We examined in rat: (1) the time-course and magnitude of change in cortical blood flow (CoBF) following electrical stimulation of the dorsal raphe nucleus (DRN) and (2) whether DRN lesions affect resting CoBF or the cerebrovascular response to CO2. Animals were anesthetized (chloralose), paralyzed, and artificially ventilated. The effect of stimulus frequency (1-200 Hz) and intensity (10-100 microA) on arterial pressure, heart rate, and CoBF was examined; lesions were made electrolytically. CoBF was measured using a laser-Doppler flowmeter with the probe placed extradurally over the parietal sensorimotor cortex. The DRN was computer reconstructed in three dimensions from Nissl stained coronal sections for localization of electrode placements. Brief stimuli (8 s; n = 6) elicited frequency and intensity-dependent increases in arterial pressure, heart rate, and CoBF. Sustained intermittent trains of stimuli of rostral DRN (200 Hz; 1 s on/1 s off; 70 microA) elicited a decrease (85 +/- 12% of baseline; n = 9) in CoBF (p less than 0.05) while stimulation in caudal DRN resulted in increased CBF (126 +/- 13% of baseline; n = 9). Phenylephrine infusion (0.1-1 microgram; i.v.; n = 8) increased arterial pressure and CoBF less than that elicited by brief DRN stimulation (p less than 0.05). DRN lesions did not affect resting CoBF (140 +/- 25 perfusion units (PU) before; 127 +/- 16 PU after DRN lesion; p greater than 0.05, n = 5) or mean arterial pressure (127 +/- 13 before; 120 +/- 11 after); nor did it affect the cerebrovascular response to change in arterial PCO2. Sustained intermittent stimulation of the DRN can evoke either increases or decreases in CoBF depending on the anatomical sublocalization. The DRN does not tonically maintain resting CoBF, nor participate in the cerebrovascular response to change in PCO2.

Distribution of neuropeptide Y immunoreactivity in human visual cortex and underlying white matter

Immunocytochemical techniques have been used to study neuropeptide Y (NPY) distribution in the human visual cortex (Brodman's areas 17, 18 and 19) NYP cell bodies belong mostly to inhibitory (multipolar and bitufted) but also to excitatory (bipolar and some pyramidal) neuronal types. Their distribution is similar in the three cortical areas studied: 20 to 40% of the NPY perikarya are located in the cortical gray matter, mostly in the deep layers, while the remaining 60 to 80% are located in the underlying white matter. Immunoreactive NPY processes form a rich network of intersecting fibers throughout the entire visual cortex. A superficial plexus (layers I and II) and a deep plexus (deep layer V and layer VI) of NPY fibers are present in areas 17, 18 and 19. In area 17, an additional well developed plexus is present in layers IVb and IVc. These plexuses receive branches from long parallel fibers arising from deep cortical layers or underlying white matter and terminating in superficial layers. Local or extrinsic NPY terminals wind around vessels in the cortex as well as in the white matter, and either penetrate them or form clusters of club endings on their walls. Our results suggest a role for NPY in human visual circuitry and in cortical blood flow regulation.

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.

Cortical blood flow regulation during hypoxemia in experimental head injury

The mechanism of increased susceptibility of the traumatized brain to hypoxemia (HYP) was investigated by measuring the local cortical blood flow (LCBF) by hydrogen clearance. Following pentobarbital anesthesia and head injury (HI) using a repetitive acceleration/deceleration injury, five surviving cats were ventilated to maintain arterial PCO 2 (28.3 ± 1.8 Torr, mean ± SEM). Three control (C) animals received no head injury. LCBF (ml/min/100 g) measurements at two cortical locations were made between 30 and 60 min postinjury, at 10 min and 40 min of HYP ( P aO 2 = 29.5 ± 2.6 Torr), and at 30-min intervals for 4.5 hr after HYP. Before HYP, LCBF was not different in cortical areas in C (84 ± 12 ml/min/100 g) and HI (81 ± 17 ml/min/100 g) animals. In C animals LCBF increased to 141 ± 10 after 10 min of HYP and remained elevated at 40 min ( P < 0.05). Ten minutes post-HYP, LCBF fell to 56 ± 8 ml/min/100 g. Hypoxemia did not increase LCBF significantly in HI animals (87 ± 17 ml/min/100 g). Post-HYP, LCBF in HI animals remained unchanged. In 78% of HI LCBF measurements, clearances following a brief H 2 inhalation were faster than clearances following tissue equilibration with H 2. This may be due to nonhomogeneous tissue perfusion in HI animals. In conclusion, after head injury there may be an attenuated microvascular blood flow response to hypoxemia and flow inhomogeneities which will accentuate tissue hypoxia.

Effects of severe arterial hypocapnia on regional blood flow regulation, tissue PO2 and metabolism in the brain cortex of cats.

The effect of a stepwise decrease in PaCO2 from 3.9-1.6 kPa on rCBF, rCMRO2, tissue PO2 and concentrations of glucose, lactate, pyruvate, ATP, ADP, AMP and phosphocreatine in the brain cortex was studied in cats lightly anaesthetized with sodium pentobarbital. 1. Moderate lowering of PaCO2 to 2.5 kPa induced in all animals a homogeneous decrease of rCBF in corresponding areas of the right and left hemisphere. Mean rCBF fell from 129.2 to 103.1 ml X 100 g-1 X min-1, while rCMRO2 remained unchanged (12.7-12.9 ml X 100 g-1 X min-1). The tissue PO2 frequency histograms showed a shift to lower values without indicating the presence of brain tissue hypoxia. 2. Severe arterial hypocapnia (PaCO2 = 1.6 kPa) caused an inhomogeneous blood flow reaction. Both further decreased as well as increased rCBF values were measured simultaneously in the brain cortex of individual animals (mean rCBF = 97.6 ml X 100 g-1 X min-1). At the same time tissue PO2 measurements and metabolite assays indicated the presence of pronounced brain tissue hypoxia. The tissue concentrations of lactate and pyruvate and the lactate/pyruvate ratio were significantly increased, while the phosphocreatine concentration was significantly reduced. In addition, rCMRO2 decreased to 11.3 ml X 100 g-1 X min-1. The results provide conclusive evidence that severe arterial hypocapnia leads to an insufficient O2 supply of the brain cortex, which in turn seems to counteract the influence of hypocapnia on cortical blood flow regulation.