Cortical Cortical Cerebral Blood Flow Research Articles

Altered Cerebral Blood Flow and Potential Neuroprotective Effect of Human Relaxin-2 (Serelaxin) During Hypoxia or Severe Hypovolemia in a Sheep Model.

Specific neuroprotective strategies to minimize cerebral damage caused by severe hypoxia or hypovolemia are lacking. Based on previous studies showing that relaxin-2/serelaxin increases cortical cerebral blood flow, we postulated that serelaxin might provide a neuroprotective effect. Therefore, we tested serelaxin in two emergency models: hypoxia was induced via inhalation of 5% oxygen and 95% nitrogen for 12 min; thereafter, the animals were reoxygenated. Hypovolemia was induced and maintained for 20 min by removal of 50% of the total blood volume; thereafter, the animals were retransfused. In each damage model, the serelaxin group received an intravenous injection of 30 µg/kg of serelaxin in saline, while control animals received saline only. Blood gases, shock index values, heart frequency, blood pressure, and renal blood flow showed almost no significant differences between control and treatment groups in both settings. However, serelaxin significantly blunted the increase of lactate during hypovolemia. Serelaxin treatment resulted in significantly elevated cortical cerebral blood flow (CBF) in both damage models, compared with the respective control groups. Measurements of the neuroproteins S100B and neuron-specific enolase in cerebrospinal fluid revealed a neuroprotective effect of serelaxin treatment in both hypoxic and hypovolemic animals, whereas in control animals, neuroproteins increased during the experiment. Western blotting showed the expression of relaxin receptors and indicated region-specific differences in relaxin receptor-mediated signaling in cortical and subcortical brain arterioles, respectively. Our findings support the hypothesis that serelaxin is a potential neuroprotectant during hypoxia and hypovolemia. Due to its preferential improvement of cortical CBF, serelaxin might reduce cognitive impairments associated with these emergencies.

Perfusion reduction in the absence of structural differences in cognitively impaired versus unimpaired RRMS patients

Background: Cognitive impairment affects 40%–68% of relapsing-remitting multiple sclerosis (RRMS) patients. Gray matter (GM) demyelination is complicit in cognitive impairment, yet cortical lesions are challenging to image clinically. We wanted to determine whether cortical cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) differences exist between cognitively impaired (CI) and unimpaired (NI) RRMS. Methods: Prospective study of healthy controls (n = 19), CI (n = 20), and NI (n = 19) undergoing magnetic resonance imaging (MRI) and cognitive testing <1 week apart. White matter (WM) T2 hyperintense lesions and T1 black holes were traced. General linear regression assessed the relationship between lobar WM volume and cortical and WM CBF, CBV, and MTT. Relationship between global and lobar cortical CBF, CBV, and MTT and cognitive impairment was tested using a generalized linear model. Adjusted Bonferroni p < 0.005 was considered significant. Results: No significant differences for age, gender, disease duration, and any fractional brain or lesion volume were demonstrated for RRMS subgroups. Expanded Disability Status Scale (EDSS) and Hospital Anxiety and Depression Scale–Depression (HADS-D) were higher in CI. Lobar cortical CBF and CBV were associated with cognitive impairment (p < 0.0001) after controlling for confounders. Cortical CBV accounted for 7.2% of cognitive impairment increasing to 8.7% with cortical CBF (p = 0.06), while WM and cortical CBF accounted for 8.2% of variance (p = 0.04). Conclusion: Significant cortical CBF and CBV reduction was present in CI compared to NI in the absence of structural differences.

Regional reduction in cortical blood flow among cognitively impaired adults with relapsing-remitting multiple sclerosis patients

Purpose: Detection of cortical abnormalities in relapsing-remitting multiple sclerosis (RRMS) remains elusive. Structural magnetic resonance imaging (MRI) measures of cortical integrity are limited, although functional techniques such as pseudo-continuous arterial spin labeling (pCASL) show promise as a surrogate marker of disease severity. We sought to determine the utility of pCASL to assess cortical cerebral blood flow (CBF) in RRMS patients with (RRMS-I) and without (RRMS-NI) cognitive impairment. Methods: A total of 19 age-matched healthy controls and 39 RRMS patients were prospectively recruited. Cognition was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Cortical CBF was compared between groups using a mass univariate voxel-based morphometric analysis accounting for demographic and structural variable covariates. Results: Cognitive impairment was present in 51.3% of patients. Significant CBF reduction was present in the RRMS-I compared to other groups in left frontal and right superior frontal cortex. Compared to healthy controls, RRMS-I displayed reduced CBF in the frontal, limbic, parietal and temporal cortex, and putamen/thalamus. RRMS-I demonstrated reduced left superior frontal lobe cortical CBF compared to RRMS-NI. No significant cortical CBF differences were present between healthy controls and RRMS-NI. Conclusion: Significant cortical CBF reduction occurs in RRMS-I compared to healthy controls and RRMS-NI in anatomically significant regions after controlling for structural and demographic differences.

Increase of cortical cerebral blood flow and further cerebral microcirculatory effects of Serelaxin in a sheep model.

Serelaxin, recombinant human relaxin-2, modulates endothelial vasodilatory functionality and is under evaluation for treatment of acute heart failure. Little is known about acute effects on cerebral perfusion. We tested the hypothesis that Serelaxin might also have effects on the cerebral microcirculation in a sheep model, which resembles human brain structure quite well. We used laser Doppler flowmetry and sidestream dark-field (SDF) imaging techniques, which are reliable tools to continuously assess dynamic changes in cerebral perfusion. Laser Doppler flowmetry shows that bolus injection of 30 μg Serelaxin/kg body wt induces an increase (P = 0.006) to roughly 150% of cortical cerebral blood flow (CBF), whereas subcortical CBF remains unchanged (P = 0.688). The effects on area-dependent CBF were significantly different after the bolus injection (P = 0.042). Effects on cortical CBF were further confirmed by SDF imaging. The bolus injection of Serelaxin increased total vessel density to 127% (P = 0.00046), perfused vessel density to 145% (P = 0.024), and perfused capillary density to 153% (P = 0.024). Western blotting confirmed the expression of relaxin receptors RXFP1 and truncated RXFP2-variants in the respective brain regions, suggesting a possible contribution of RXFP1 on the effects of Serelaxin. In conclusion, the injection of a high dose of Serelaxin exerts quick effects on the cerebral microcirculation. Therefore, Serelaxin might be suitable to improve cortical microcirculation and exert neuroprotective effects in clinically relevant scenarios that involve cortical hypoperfusion. These findings need to be confirmed in relevant experimental settings involving cerebral cortical hypoperfusion and can possibly be translated into clinical practice.

Quantitative Lobar Cerebral Blood Flow for Outcome Prediction after Traumatic Brain Injury

The aim of this study was to examine cortical cerebral blood flow (CBF) in patients with traumatic brain injury (TBI) and determine whether lobar cortical CBF is a better predictor of long-term neurological outcome assessed by the Glasgow Outcome Scale (GOS) than global cortical CBF. Ninety-eight patients with TBI had a stable xenon computed tomography scan (Xe/CT-CBF study) performed at various time points after their initial injury. Spearman's correlation coefficients and Kruskall-Wallis' test were used to examine the relationship between patient age, emergency room Glasgow Coma Scale (GCS), Injury Severity Score, prehospital hypotension, prehospital hypoxia, mechanism of injury, type of injury, side of injury, global average CBF, lobar CBF, number of lobes with CBF below normal, and GOS (discharge, 3 and 6 months). Univariate ordinal regression was performed using these same variables and in combination with principle component analysis (PCA) to determine independent variables for multi-variate ordinal regression. Significant correlation between age, GCS, prehospital hypotension, type of injury, global average CBF, lobar CBF, number of lobes below normal CBF, and GOS was found. Individual lobar CBF was highly correlated with global CBF and the number of lobes below normal CBF. PCA found one principle component among these three CBF variables; therefore, average global CBF and number of lobes with CBF below normal were each chosen as independent variables for multiple ordinal regression, which found age, GCS, and prehospital hypotension, global average CBF, and number of lobes below normal CBF significantly associated with GOS. This study found global average CBF and lobar CBF significantly correlated with GOS at follow-up. There was, however, no individual cerebral lobe that was more predictive than any other, which puts into question the value of calculating lobar CBF versus global CBF in predicting GOS.

Xe-CT and transcranial doppler in symptomatic vasospasm subarachnoid hemorrhage patients under euvolemic treatment without sedation

Delayed cerebral ischemia from cerebral arterial vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) is associated with significant morbidity and mortality. Early recognition of the cerebral arterial vasospasm and institution of appropriate treatment can reduce the consequences. We investigated the association of transcranial Doppler (TCD) and Xe-CT with the characteristics of symptomatic vasospasm secondary to aneurysmal subarachnoid hemorrhage (SAH) in patients who underwent euvolemic treatment without sedation. Data collected prospectively in patients with aSAH admitted to a neurocritical care unit in a regional hospital were retrospectively analyzed. Out of the 98 consecutive patients with aSAH, 30 patients underwent paired Xe-CT (not sedated) and TCD studies. Correlation between cortical cerebral blood flow (CBF) and mean blood flow velocity in middle cerebral artery (MCA) territories was analyzed. The lowest cortical regional CBF and MCA velocity were compared between patients with and without symptomatic vasospasm. Symptomatic vasospasm occurred in 12 patients. No correlation was found between CBF and mean blood flow velocity of the MCA territory. The differences between MCA velocity and lowest cortical CBF in patients with symptomatic vasospasm were significantly different from patients without symptoms. TCD does not help to predict regional CBF in the MCA territory in patients with aSAH on euvolemic treatment.

Alterations in cerebral cortex microvessels and the microcirculation in a rat model of traumatic brain injury: a correlative EM and laser Doppler flowmetry study

Objectives: We sought to establish the temporal association of fluctuations in cortical cerebral blood flow (CBF) with ultrastructural alterations of microvessels in rat sensorimotor cortex (smCx) following administration of a rodent acceleration impact model of traumatic brain injury (TBI).Methods: Laser Doppler flowmetry (LDF) and electron microscopy (EM) were used in parallel experiments that lasted for up to 48 hours after induction of TBI.Results: Compared to sham-operated control, there was a 37% reduction of cortical CBF between 12 and 24 hours, this reduction remaining unchanged for up to 48 hours post-TBI. Ultrastructural alterations in the lumen and wall of smCx microvessels, including endothelial cell distortion and luminal collapse, were seen at hour 1 and continued up to 48 hours after trauma. Compared to control, there was a 40% decrease in the average microvascular luminal area 4 hours and a trend to recover (21%) by 48 hours after trauma. Smooth muscle (SM) in the wall of reacting microvessels showed evidence of increase contractility that coincided temporally with the decreased perfusion of cortical CBF.Discussion: Based on these observations, it is proposed that TBI causes alterations in the vascular tone of reacting microvessels which leads to prolonged vasoreactivity and restriction of the lumen in many but not all microvessels.

Real-time cortical cerebral blood flow follow-up in conscious, freely moving rats by laser Doppler flowmetry

This article describes a laser Doppler flowmetry (LDF) system that enables repeated measurements and thereby long-term followup of cortical cerebral blood flow (CBF) in awake and freely moving rats. The system consists of a specially designed flow probe adapter, a flow probe connector, and a LDF flow probe, which may thereby rotate through its own axis. During the experiment, the flow adapter is permanently mounted onto the rat’s skull bone. A thin layer of skull bone is left intact at the site for cortical CBF measurements. The probe connector and the flow probe may be repeatedly detached and remounted to the adapter, which allows for cortical cerebral blood flow recording from exactly the same anatomical location. The laser Doppler flowmetry system enables stable cortical CBF recordings in the conscious rat while it moves freely in a bowl cage.

Nicotine-induced NO-mediated increase in cortical cerebral blood flow is blocked by β 2-adrenoceptor antagonists in the anesthetized rats

Involvement of nitric oxide (NO) and β-adrenoceptors in an increase in the cortical cerebral blood flow (CBF) following an intravenous (i.v.) injection of a small dose of nicotine which did not affect the systemic blood pressure in the rats was investigated. I.v. injection of nicotine (30 μg/kg) for 1 min produced a significant increase in CBF lasting for more than 20 min without a significant effect on the systemic blood pressure. I.v. injection of l- N G-nitroarginine methylester (30 mg/kg) significantly attenuated nicotine-induced increase in the cortical CBF. The attenuation was reversed by i.v. injection of l-arginine (300 mg/kg), suggesting an intimate role of nitric oxide (NO) in nicotine-induced increase in the cortical CBF. The nicotine-induced increase in the cortical CBF was significantly attenuated by propranolol (10 mg/kg, i.v.) and ICI 118, 551 (a β 2-adrenoceptor antagonist, 10 mg/kg, i.v.) but not by metoprolol (a β 1-adrenoceptor antagonist, 10 mg/kg, i.v.). β 2-adrenoceptors on presynaptic nitrergic nerves may be involved in nicotine-induced NO-mediated increase in the cortical CBF.

Temporal lobe seizure interhemispheric propagation time depends on nonepileptic cortical cerebral blood flow

In some patients with epilepsy, activation of eloquent cortex using various forms of environmental stimulation and mental activity may induce seizures. The increased neuronal activity resulting from cortical stimulation may be associated with increased regional cerebral blood flow. The vascular steal theory of temporal lobe epilepsy suggests that as nonepileptogenic cortical cerebral blood flow (CBFn) increases, temporal lobe epileptogenicity increases as a result, in part, of decreasing interhemispheric propagation time (IHPT). Recently, IHPT has been shown to be a quantitative electrocorticographic measure of temporal lobe epileptogenicity. In the current study, long-term combined subdural-EEG and surface cortical cerebral blood flow (CBF) monitoring was performed to test the hypothesis that IHPT depends upon CBFn. The results show that IHPT is a nonlinear (negative exponential) function of nonepileptic cortical CBF ( r=0.507, df=32, t=−2.204, P<0.05). In temporal lobe epilepsy, nonepileptic cortical hypoperfusion may represent a protective mechanism for delaying interhemispheric seizure propagation. The fact that IHPT decreases exponentially with increasing CBFn suggests that small increases in CBFn should substantially decrease IHPT and increase epileptogenicity. This study confirms that inter-hemispheric propagation time depends upon perfusion of nonepileptogenic cortex.

Effects of dopamine on posttraumatic cerebral blood flow, brain edema, and cerebrospinal fluid glutamate and hypoxanthine concentrations.

Dopamine is often used in the treatment of traumatic brain injury to maintain cerebral perfusion pressure. However, it remains unclear whether dopamine contributes to secondary brain injury caused by vasoconstriction and resulting diminished cerebral perfusion. The present study investigated the effects of dopamine in different concentrations on posttraumatic cortical cerebral blood flow (CBF), brain edema formation, and cerebrospinal fluid concentrations of glutamate and hypoxanthine. Randomized, placebo-controlled trial. Animal laboratory. Eighteen male Sprague-Dawley rats subjected to a focal cortical brain injury. Four hours after controlled cortical impact, rats were randomized to receive physiologic saline solution (n = 6), 10-12 tig/kg/min dopamine (n = 6), or 40-50 microg/kg/min dopamine (n = 6), for 3 hrs. Cortical CBF was measured over both hemispheres by using laser-Doppler flowmetry before trauma and before, during, and after the infusion period. At 8 hrs after trauma, brains were removed to determine hemispheric swelling and water content. Cisternal cerebrospinal fluid was sampled to measure glutamate and hypoxanthine. After trauma, cortical CBF was significantly decreased by 46% within the vicinity of the cortical contusion in all rats. Infusion of saline and 10-12 ig/kg/min dopamine did not change mean arterial blood pressure (MABP) or cortical CBF. However, infusion of 40-50 microg/kg/min dopamine, which elevated MABP from 89 to 120 mm Hg, significantly increased posttraumatic CBF within and around the contusion by 35%. Over the nontraumatized hemisphere, CBF remained unchanged. Hemispheric swelling, water content, cerebrospinal fluid glutamate, and hypoxanthine levels were not affected by dopamine in the given dosages. Under the present study design, there was no evidence for a dopamine-mediated vasoconstriction, because posttraumatic cortical CBF was increased by dopamine-induced elevation of MABP. However, the increase in CBF did not significantly affect edema formation or cerebrospinal fluid glutamate and hypoxanthine levels.

Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats.

Estrogen-related neuroprotection in association with animal models of transient forebrain and focal ischemia has been documented in several recent reports. Some of those studies indicated that part of that benefit was a function of improved intraischemic vasodilating capacity. In the present study we examined whether chronic estrogen depletion and repletion affected ischemic neuropathology through perfusion-independent mechanisms. Normal, ovariectomized (OVX), and OVX female rats treated with 17beta-estradiol (E2) were subjected to 30 minutes of transient forebrain ischemia (right common carotid occlusion plus hemorrhagic hypotension) and reperfusion. Neurological function and brain histopathology were assessed over the 72-hour recovery period. In all rats, preischemic and intraischemic cortical cerebral blood flow (CBF) levels were monitored with laser-Doppler flowmetry. In additional rats, CBF changes in the striatum and hippocampus were also monitored with laser-Doppler flowmetry probes and radiolabeled microspheres. In each experiment, the level of ischemia was targeted to a 75% to 80% reduction in cortical CBF. The similarity in ischemic severity among groups was supported by measurements of comparable patterns of electroencephalographic power changes during the ischemic period. Compared with normal females, OVX rats showed diminished neurological outcomes and more severe histopathology in the hippocampus and striatum. Two-week treatment of OVX rats with E2 was accompanied by postischemic neuropathological changes similar to those seen in normal females. Intraischemic CBF reductions in the hippocampus and striatum were similar in all groups (to 35% to 50% of the preischemic value) but significantly less than the cortical CBF reductions. These findings indicate that estrogen provides ischemic neuroprotection through mechanisms unrelated to improvement of intraischemic cerebral perfusion.

Effect of stimulation of nicotinic cholinergic receptors on cortical cerebral blood flow and changes in the effect during aging in anesthetized rats

The effect of intravenous injection of nicotine on cortical cerebral blood flow (CBF) was examined in urethane anesthetized rats. Nicotine (3–30 μg/kg) increased cortical CBF, independent of mean arterial pressure. This response was attenuated to about a half of the control one after lesioning the nucleus basalis of Meynert (NBM) bilaterally. The response was not significantly influenced after blocking the muscarinic receptors, but was abolished after blocking the nicotinic receptors in the parenchyma of the brain. It is concluded that the nicotine-induced cortical vasodilation was mediated by activation of the nicotinic receptors in the NBM and also in the cortex of the brain. The threshold dose of nicotine for increasing cortical CBF was shifted in aged rats of 23–26 months, and the nicotine-induced increase in cortical CBF was much reduced in aged rats of 32–36 months. Activation of nicotinic receptors in the brain may be of therapeutic value in aged subjects in facilitating the cholinergic neural vasodilative system.

Neuronal NO promotes cerebral cortical hyperemia during cortical spreading depression in rabbits.

Temporary elevations in cortical cerebral blood flow (CBF) accompany cortical spreading depression (CSD) in anesthetized animals. We tested the hypothesis that nitric oxide (NO) is an important promotor of CSD-induced cortical hyperemia in urethan-anesthetized rabbits. CBF was measured at four time points by administration of 15-microm microspheres with the reference withdrawal technique. Intravenous administration of the nonspecific NO synthase (NOS) inhibitor N(omega)-nitro-L-arginine increased mean arterial blood pressure and resting cerebrovascular resistance and attenuated CSD-induced hyperemia. Cortical CBF before intraperitoneal 7-nitroindazole (7-NI), a neuronal NOS inhibitor, was 42 +/- 8 and 124 +/- 19 ml x 100 g(-1) x min(-1) at baseline and during CSD, respectively (P < 0.05 by repeated-measures analysis of variance). After 7-NI administration, mean arterial blood pressure, CBF, and cerebrovascular resistance were unchanged from baseline values; cortical CBF was 38 +/- 4 and 90 +/- 8 ml x 100 g(-1) x min(-1) post-7-NI at rest and during a second CSD, respectively. Similar to N(omega)-nitro-L-arginine, 7-NI decreased the cortical hyperemic response during CSD (P < 0.05 by repeated-measures analysis of variance). We conclude that neuronal NOS promotes the temporary cortical hyperemia observed during CSD.

The effects of a carotid-jugular fistula on cerebral blood flow in the cat: an experimental study in the chronic period.

The purpose of the present study was to investigate the effects of feline carotid-jugular fistula (Spetzler's model) on cerebral blood flow at 8 weeks after creation of the fistula. Using laser-Doppler flowmetry, cortical cerebral blood flow (CBF) on the fistula side was measured in 10 cats, Occlusion of the fistula showed no cortical CBF changes in 6 animals, but transient increases in 4. CO2 reactivity in the closed fistula was preserved. No neurological or histological abnormalities were recognized. These findings suggested that cerebral hemodynamic changes due to Spetzler's CJ fistula model are minimal even in the chronic period after fistulization. Therefore, creation of another experimental arterio-venous fistula model is mandatory for the investigation of hemodynamic changes following resection of a cerebral arteriovenous malformation.

Response of human epileptic temporal lobe cortical blood flow to hyperventilation.

Bilateral long-term surface cortical cerebral blood flow (CBF) and electrocorticographic (ECoG) monitoring were performed in eight patients with complex partial seizures. In each patient, the epileptic temporal lobe was localized using ictal ECoG. Mean seizure interval (frequency-1) off anticonvulsant medication, a clinical measure of epileptogenicity, was 1.0 +/- 0.3 h (range: 0.4 to 2.5 h). During 13 interictal hyperventilation periods, 3.6 +/- 0.6 min in duration, the mean decrease in epileptic and nonepileptic temporal cortical CBF was 13.7 +/- 2.3 versus 6.4 +/- 1.9 ml/(100 g min) (t = 2.230, d.f. = 16, P < 0.05), representing 20.9% and 10.8% reduction from baseline CBF during hyperventilation, respectively. Seizure interval decreased (i.e. frequency increased) with increasing magnitude of seizure focus CBF reduction during hyperventilation. Seizure interval was significantly correlated with epileptic temporal lobe CBF decrease during hyperventilation (R = 0.763, d.f. = 5, P < 0.05). The data suggest that, compared to nonepileptic brain, epileptic temporal lobe is particularly prone to hypoperfusion during hyperventilation. Epileptogenicity is a function of this seizure focus susceptibility to ischemia. The finding of abnormal seizure focus autoregulation during hyperventilation has implication for epileptic focus localization with cerebral blood flow analysis.

Alpha-Phenyl N-tert-butyl nitrone (PBN) increases the cortical cerebral blood flow by inhibiting the breakdown of nitric oxide in anesthetized rats.

The effects of intravenous administration of alpha-phenyl N-tert-butyl nitrone (PBN) on cortical cerebral blood flow (CBF) were examined in Wistar rats under pentobarbital anesthesia and artificial ventilation. The cortical CBF in parietal cortex was measured by laser Doppler flowmetry. Intravenous administrations of 2 mg/kg and 20 mg/kg of PBN dose-dependently produced significant increases in cortical CBF and decreases in systemic blood pressure (BP). To examine whether these increased responses in cortical CBF produced by PBN were associated with the vasodilatation system of nitric oxide (NO), the NO synthase inhibitor L-NG-nitroarginine (L-NOArg), which is an analog of L-arginine, was used to inhibit the NO-related-vasodilatative system. Since the PBN-induced responses in the cortical CBF were much attenuated in L-NOArg-treated rats (30 mg/kg, i.v.), it was inferred that NO-related vasodilatation was strongly associated with the PBN-induced increase in cortical CBF.

Basal forebrain control of cortical cerebral blood flow is independent of local cortical neurons

To determine whether intrinsic cortical neurons participate in mediating increases in cortical cerebral blood flow (CBF) in response to electrical stimulation of the basal forebrain (BF), cortical CBF was assessed by laser-DOppler flowmetry in rats before and after unilaterally removing local cortical neurons with the excitotoxin ibotenic acid (IBO). On the first day of testing, CBF responses to right and left BF stimulation were nearly identical in right and left frontal cortices, corresponding to the frequency of stimulation, up to a maximum at 25 Hz (+180%). Subsequently, animals received a unilateral microinjection of IBO and a contralateral microinjection of phosphate-buffered saline (PBS) into the responsive cortical sites. After five days, responses in lesioned cortices were remarkably intact both in comparison to the contralateral PBS-injected site and to the same site tested prior to lesioning on day 1. IBO lesions of the response sites were histologically confirmed to extend through the entire depth of the frontal cortex and to encompass a large surface area ( 7.7 ± 0.5mm 2 ). These results indicate that local cortical neurons are not critical to the mediation of increases in cortical CBF as elicited by BF stimulation. This study further supports the role of the BF as a distinct intracerebral neurogenic regulator of cortical CBF.

Nitric oxide synthase is critical in mediating basal forebrain regulation of cortical cerebral circulation.

This study sought to determine whether the activity of nitric oxide synthase (NOS) is an important physiological link required to mediate increases in cortical cerebral blood flow (CBF) elicited by electrical microstimulation of the basal forebrain (BF). Changes in cortical CBF were assessed in urethane anesthetized rats using laser-Doppler flowmetry. Microstimulation of the BF elicited stimulus-locked increases in CBF that were dependent on frequency and current intensity (up to 280% of control at 50 Hz). Infusion of the potent NOS inhibitor NG-nitro-L-arginine (L-NNA) resulted in significant dose-related reductions in the BF-elicited response at 50 Hz (3.75-60 mg/kg, i.v.), significant elevation in resting mean arterial pressure (MAP) from 106 to 160 mmHg, and modest 21% reductions in resting CBF. The stereoisomer NG-nitro-D-arginine (D-NNA) was without any effect on CBF, although at higher concentrations MAP was elevated to levels comparable to those obtained with L-NNA. Infusion of arginase was also without effect on resting or BF-elicited CBF responses. In contrast, L-arginine (100-400 mg/kg, i.v.) significantly potentiated the BF-elicited response up to an additional 38%, without affecting resting CBF or MAP. This study suggests that NO, or a related nitroso precursor formed by NOS, has a critical role in mediating regulation of cortical CBF by BF neurons.

Heptyl-physostigmine enhances basal forebrain control of cortical cerebral blood flow.

This study sought to determine the effect of heptylphysostigmine (H-PHY), a reversible cholinesterase (ChE) inhibitor with greater lipophilicity and longer duration of action than physostigmine, on resting and basal forebrain (BF)-elicited increases in cortical cerebral blood flow (CBF). Laser-doppler flowmetry (LDF) was used to monitor changes in frontal cortical microvascular perfusion in urethane anesthetized rats. Responses were measured before, early after, and 1 hr following H-PHY, 3 mg/kg, i.m. Electrical stimulation (100 microA) of the BF elicited up to 220% increases in CBF at 50 Hz, an effect that was graded with frequency. At 15 min following H-PHY (3 mg/kg) resting cortical CBF was unchanged, whereas BF-elicited increases were potentiated 47% at 50 Hz. At 1 hour, resting cortical CBF remained unchanged, and the BF-elicited responses were remarkably potentiated by 354% at 10 Hz and 67% at 50 Hz. Acetylcholinesterase (AChE) activity measured in the tissue directly beneath the LDF probe was decreased by 84% at a time when these CBF responses were enhanced. These data suggest that H-PHY substantially enhances the regulation of cortical CBF by the BF, an effect that may be linked to inhibition of cortical AChE activity. This enhancement of cortical CBF may contribute to the efficacy of H-PHY as a treatment for Alzheimer's disease.