Maintenance Of Cerebral Blood Flow Research Articles

Evaluation of markers of cerebral oxygenation and metabolism in patients undergoing clipping of cerebral aneurysm under total intravenous anesthesia versus inhalational anesthesia: A prospective randomized trial (COM-IVIN trial).

Anesthetic goals in patients undergoing clipping of cerebral aneurysm include maintenance of cerebral blood flow, oxygenation, and metabolism to avoid cerebral ischemia and maintenance of hemodynamic stability. We intend to study the influence of anesthetic agents on the outcome of aneurysmal subarachnoid hemorrhage (SAH). This is a prospective, randomized, parallel, single-center pilot trial approved by the Institutional Ethics Committee and is prospectively registered with the Clinical Trial Registry of India. Patients with aneurysmal SAH (aSAH) admitted to our institution for surgical clipping, fulfilling the trial inclusion criteria, will be randomized in a 1:1 allocation ratio utilizing a computerized random allocation sequence to receive either total intravenous anesthesia (n = 25) or inhalational anesthesia (n = 25). Our primary objective is to study the effects of these anesthetic techniques on cerebral oxygenation and metabolism in patients with aSAH. Our secondary objective is to evaluate the impact of these anesthetic techniques on the incidence of delayed cerebral ischemia and long-term patient outcomes in patients with aSAH. The Modified Rankin Score and Glasgow Outcome Scale (GOS) at discharge and 3 months following hospital discharge will be evaluated. An observer blinded to the study intervention will assess the outcome measures. This study will provide more insight as to which is the ideal anesthetic agent that offers a better neurophysiological profile regarding intraoperative cerebral oxygenation and metabolism, thereby contributing to better postoperative outcomes in aSAH patients.

Abstract 196: Association Between Continuous Carotid Blow Flow And Continuous Cerebral Perfusion Indexes Assessment By NIRS In A Porcine Model Of Ventricular Fibrillation During CPR

[Background]: Maintenance of cerebral blood flow during cardiopulmonary resuscitation (CPR) is a critical factor affecting the neurological outcome of patients after cardiac arrest. However, dynamic indicator of cerebral blood flow during CPR is not established. Near infrared spectroscopy (NIRS) is a non-invasive technique capable of detecting changes in cerebral blood volume continuously. The aim of this study is to compare cerebral perfusion during CPR obtained by continuous measure of carotid blow flow (CBF) using flow sensor with continuous cerebral perfusion indices (CPI) assessment by NIRS in a porcine model of ventricular fibrillation (VF) cardiac arrest. [Methods]: CBF during CPR were measured in 21 swine (25± 3 kg) using extra-vascular flow probes positioned around the common carotid arteries. The optodes of the NIRS were attached to the skull bone. Following baseline measurements, VF was electrically induced. After the interval of untreated VF, CPR was continued for 25 min, during which mechanical and manual CPR was alternated at every 5 min intervals. CBF and CPI were measured continuously during CPR. The mean volume of CBF and CPI was calculated average 10 beats in each phase. Correlations between CBF volume and CPI were analyzed by Spearman's rank correlation. [Results]: The followability of CBF and CPI during CPR was good. The Spearman's rank correlation coefficient between CBF volume and CPI was different by sections and it was suggested that the CBF volume was too small to assess the correlation in many sections. If the sections with CBF volume>0.4 ml were extracted and reanalyzed, the rate of sections correlated between CBF volume and CPI were increased (Spearman’s correlation coefficient≧0.4 was 41.3%, Spearman’s correlation coefficient≧0.7 was 17.5%).(Table) [Conclusions]: It was suggested that CPI by NIRS can reflect the CBF during CPR in the sections where enough CBF is.

Cerebrovascular Gi Proteins Protect Against Brain Hypoperfusion and Collateral Failure in Cerebral Ischemia

Cerebral hypoperfusion and vascular dysfunction are closely related to common risk factors for ischemic stroke such as hypertension, dyslipidemia, diabetes, and smoking. The role of inhibitory G protein-dependent receptor (GiPCR) signaling in regulating cerebrovascular functions remains largely elusive. We examined the importance of GiPCR signaling in cerebral blood flow (CBF) and its stability after sudden interruption using various in vivo high-resolution magnetic resonance imaging techniques. To this end, we induced a functional knockout of GiPCR signaling in the brain vasculature by injection of pertussis toxin (PTX). Our results show that PTX induced global brain hypoperfusion and microvascular collapse. When PTX-pretreated animals underwent transient unilateral occlusion of one common carotid artery, CBF was disrupted in the ipsilateral hemisphere resulting in the collapse of the cortically penetrating microvessels. In addition, pronounced stroke features in the affected brain regions appeared in both MRI and histological examination. Our findings suggest an impact of cerebrovascular GiPCR signaling in the maintenance of CBF, which may be useful for novel pharmacotherapeutic approaches to prevent and treat cerebrovascular dysfunction and stroke.

Optical monitoring of cerebral perfusion and metabolism in adults during cardiac surgery with cardiopulmonary bypass.

During cardiac surgery with cardiopulmonary bypass (CPB), adequate maintenance of cerebral blood flow (CBF) is vital in preventing postoperative neurological injury - i.e. stroke, delirium, cognitive impairment. Reductions in CBF large enough to impact cerebral energy metabolism can lead to tissue damage and subsequent brain injury. Current methods for neuromonitoring during surgery are limited. This study presents the clinical translation of a hybrid optical neuromonitor for continuous intraoperative monitoring of cerebral perfusion and metabolism in ten patients undergoing non-emergent cardiac surgery with non-pulsatile CPB. The optical system combines broadband near-infrared spectroscopy (B-NIRS) to measure changes in the oxidation state of cytochrome c oxidase (oxCCO) - a direct marker of cellular energy metabolism - and diffuse correlation spectroscopy (DCS) to provide an index of cerebral blood flow (CBFi). As the heart was arrested and the CPB-pump started, increases in CBFi (88.5 ± 125.7%) and significant decreases in oxCCO (-0.5 ± 0.2 µM) were observed; no changes were noted during transitions off CPB. Fifteen hypoperfusion events, defined as large and sustained reductions in CPB-pump flow rate, were identified across all patients and resulted in significant decreases in perfusion and metabolism when mean arterial pressure dropped to 30 mmHg or below. The maximum reduction in cerebral blood flow preceded the corresponding metabolic reduction by 18.2 ± 15.0 s. Optical neuromonitoring provides a safe and non-invasive approach for assessing intraoperative perfusion and metabolism and has potential in guiding patient management to prevent adverse clinical outcomes.

Traumatic Brain Injury (tbi) Attenuates Arterial Smooth Muscle Vasorelaxation In Pressurized Cerebral Arteries

Maintenance of cerebral blood flow (CBF) is impaired following traumatic brain injury (TBI), increasing the incidence of both ischemic and hemorrhagic events. Vascular tone is controlled by neurogenic, endothelial, and myogenic responses. PURPOSE: This work was designed to specifically determine the extent to which the myogenic response of vascular smooth muscle in the middle cerebral artery (MCA) is altered following TBI. METHODS: TBI was induced by controlled cortical impact (CCI) in 2-month-old male Sprague-Dawley rats. Twenty-four hours following injury or sham surgery, pressurized arterial myography was performed on endothelium-denuded MCA to examine the effect of TBI on smooth muscle-specific vasorelaxation using pharmacologic activators of the adenylyl cyclase (AC)-cAMP-PKA/PKG pathway (10-9M to 10-5M, n=6 at each dose). RESULTS: Myogenic tone was attenuated following TBI (25±1.1% vs. 18±1.2%, n=12; p<0.001). The mean change in myogenic tone in response to activators (10-6M) was reduced to 35% (AC), 33% (PKA), and 30% (PKG) in TBI as compared to sham controls. CONCLUSION: Attenuation of smooth muscle myogenic tone and resulting vasorelaxation following TBI may serve as a compensatory mechanism to protect sensitive brain tissue from cerebral ischemia. Future work will be needed to elucidate the role of pathways that could serve as potential targets for therapeutic intervention to reduce damaging vascular events. Supported by The Florida State University Graduate School Dissertation Award Grant.

Role of Heme metabolism in the oxidative state of NO‐receptor soluble guanylyl cyclase (sGC) in aging mouse brain

IntroductionAging is an important risk factor for cardiovascular diseases and neurodegeneration. Heme synthesis and metabolism decline with age. Heme moiety is essential for proper function of the Nitric Oxide receptor soluble guanylyl cyclase (sGC). Evidence suggests the involvement of NO/cGMP signaling in human neurological disorders. sGC also an important role in maintenance of cerebral blood flow, vascular homeostasis and platelet function. NO binds to the ferrous heme moiety of sGC and activates cGMP‐forming activity hundred fold. Therefore, the integrity of reduced sGC heme moiety is essential for proper transduction of NO signal.Methods and ResultsWe investigated if the oxidative state and the relative content of sGC heme moiety changes with age in mouse brain tissue. Three groups of animals have been used in our studies: young, 3.5 months old, and mature, 15 months old, and old, 24 months, C57Bl6 mice. sGC‐dependent synthesis of cGMP in protein homogenates from mouse brains in response to sGC regulators was evaluated by quantifying the amount P32‐labeled cGMP using thin layer chromatography. To estimate the changes in the amount of heme‐deficient sGC, protoporphyrin IX (PPIX) was used as a heme‐independent sGC activator. NO‐independent activator BAY 58‐2667, which has a higher affinity for sGC with ferric heme, was used to evaluate the changes in the amount of sGC with oxidized heme. NO donor DEA‐NO was used to evaluate the level of sGC with ferrous heme. For each individual sample the ratios of sGC‐[HemeFe3+] vs sGC‐[HemeFe2+] activities (BAY 58‐2667/DEA‐NO) and heme‐deficient vs sGC‐[HemeFe2+] activities (PPIX/DEA‐NO) were determined. Our analysis demonstrated that the relative amount of heme‐deficient and heme‐oxidized sGC increased in both males and females of older age. Decline in sGC protein expression in oldest animal groups was detected by Western blot analysis. We also investigated if the accumulation of heme‐deficient sGC or sGC with ferric heme in ageing brain correlates with changes in the level of proteins involved in iron and heme metabolism. We found no difference in the level of HSP90 chaperone needed for sGC heme insertion and unchanged level in the iron chaperone PCBP2, which is essential for iron trafficking. The expression of divalent metal ion transporter (DMT1) was also not affected by age. However, we observe a decrease in the expression of Heme Oxygenase 1 (HO1) and Aconitase 2 proteins involved in maintenance of cellular oxidative balance in old animals of both genders.ConclusionOur data indicate that changes in heme homeostasis might contribute to the decline of NO/sGC in brain with aging.

Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults.

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults ( n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT ( P < 0.001), but a positive quadratic trend in EX + SIT ( P < 0.001) and EX + BR ( P < 0.01). Afternoon time points in SIT were lower than baseline within condition ( P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR ( P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT ( P = 0.007) or EX + BR ( P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain. NEW & NOTEWORTHY This is the first study to measure the combined effects of an exercise bout with breaks in sitting on cerebral blood velocity in older adults. Using frequent recordings over an 8-h period, we have performed a novel analysis of the pattern of cerebral blood velocity, adjusting for concurrent measures of mean arterial pressure and other potential confounders in a linear mixed effects regression.

Dysregulation of RNF213 promotes cerebral hypoperfusion

RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.

L-Citrulline ameliorates cerebral blood flow during cortical spreading depression in rats: Involvement of nitric oxide- and prostanoids-mediated pathway

l-Citrulline is a potent precursor of l-arginine, and exerts beneficial effect on cardiovascular system via nitric oxide (NO) production. Migraine is one of the most popular neurovascular disorder, and imbalance of cerebral blood flow (CBF) observed in cortical spreading depression (CSD) contributes to the mechanism of migraine aura. Here, we investigated the effect of l-citrulline on cardiovascular changes to KCl-induced CSD. in rats. Intravenous injection of l-citrulline prevented the decrease in CBF, monitored by laser Doppler flowmetry, without affecting mean arterial pressure and heart rate during CSD. Moreover, l-citrulline attenuated propagation velocity of CSD induced by KCl. The effect of l-citrulline on CBF change was prevented by l-NAME, an inhibitor of NO synthase, but not by indomethacin, an inhibitor of cyclooxygenase. On the other hand, attenuation effect of l-citrulline on CSD propagation velocity was prevented not only by l-NAME but also by indomethacin. In addition, propagation velocity of CSD was attenuated by intravenous injection of NOR3, a NO donor, which was diminished by ODQ, an inhibitor of soluble guanylyl cyclase. These results suggest that NO/cyclic GMP- and prostanoids-mediated pathway differently contribute to the effect of l-citrulline on the maintenance of CBF.

Lessons from altitude: cerebral perfusion insights and their potential translational clinical significance

What is the topic of this review? The long-held assumption that transcranial Doppler middle cerebral artery velocity is a surrogate for cerebral blood flow has been questioned in certain circumstances, particularly where tissue oxygenation changes. What advances does it highlight? Cerebral venous outflow restriction appears to be implicated in the development of high-altitude cerebral oedema. Rapid ascent to high altitude commonly results in acute mountain sickness and, on occasion, potentially fatal high-altitude cerebral oedema. The exact pathophysiological mechanisms behind these syndromes remain to be determined. One of the main theories to explain the development of acute mountain sickness is an increase in intracranial pressure. Vasogenic (extracellular water accumulation attributable to increased permeability of the blood-brain barrier) and cytotoxic (intracellular) oedema have also been postulated as potential mechanisms that underlie high-altitude cerebral oedema. Recently published findings derived from a very challenging field study (obtained at altitudes of up to 7950m), substantiated by sea-level hypoxic magnetic resonance angiography studies, have given new insights into the maintenance of cerebral blood flow at altitude. This report provides new perspectives and potential mechanisms to account for the maintenance of cerebral oxygen delivery at high and extreme altitude. In particular, the long-held assumption that transcranial Doppler middle cerebral artery velocity is a surrogate for cerebral blood flow has been shown to be incorrect in certain circumstances. The emerging evidence for a potential third mechanism, namely the restrictive venous outflow hypothesis, in the development of high-altitude cerebral oedema, over and above the accepted vasogenic and cytotoxic hypotheses, is also appraised.

Stroke associated with coronary artery bypass grafting.

While coronary artery bypass grafting (CABG) has been playing a significant role in the revascularization for ischemic heart disease, neurological complications associated with CABG have been a primary concern. Stroke, although the incidence is low, is one of the most devastating complication of CABG. Many studies have identified the risk factors for stroke with CABG, such as prior stroke, carotid artery stenosis, aortic atherosclerosis, atrial fibrillation and cardiopulmonary bypass. Various rational approaches focusing on individual risk factor have been proposed for the stroke. Prophylactic carotid revascularization is an important strategy, and the diagnosis of carotid stenosis has to be established correctly. Prevention of emboli from aortic plaque is also an essential issue. Intraoperative monitoring with transesophageal or epiaortic ultrasound is useful to identify mobile atheromatous plaques and to select appropriate aortic manipulations. Maintenance of cerebral blood flow and blood pressure during cardiopulmonary bypass might be critical issues. Besides, there are conflicting two opinions regarding off-pump CABG; one supports an efficiency for the prevention of stroke while the other advocates no effect. This discrepancy might be explained by the difference of the risk of stroke in the population of the individual study and by the variation of the percentage of aortic clamping or aortic anastomosis in each study. Pharmaceutical therapies such as statin, preventive medication for atrial fibrillation, or antiplatelet are promising methods. Although it is hard to decrease the incidence of the stroke with any single countermeasure, sustained effort should be continued to overcome the stroke associated with CABG.

Cerebroprotective effects of RAS inhibitors: Beyond their cardio-renal actions.

Work on the brain renin-angiotensin system has been explored by various researchers and has led to elucidation of its basic physiologies and behavior, including its role in reabsorption and uptake of body fluid, blood pressure maintenance with angiotensin II being its prominent effector. Currently, this system has been implicated for its newly established effects, which are far beyond its cardio-renal effects accounting for maintenance of cerebral blood flow and cerebroprotection, seizure, in the etiology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and bipolar disorder. In this review, we have discussed the distribution of angiotensin receptor subtypes in the central nervous system (CNS) together with enzymatic pathways leading to active angiotensin ligands and its interaction with angiotensin receptor 2 (AT2) and Mas receptors. Secondly, the use of angiotensin analogues (angiotensin converting enzyme inhibitors and AT1 and/or AT2 receptor blockers) in the treatment and management of the CNS disorders mentioned above has been discussed.

Brain Tissue Oxygen Monitoring in Neurocritical Care

Brain injury results from ischemia, tissue hypoxia, and a cascade of secondary events. The cornerstone of neurocritical care management is optimization and maintenance of cerebral blood flow (CBF) and oxygen and substrate delivery to prevent or attenuate this secondary damage. New techniques for monitoring brain tissue oxygen tension (PtiO2) are now available. Brain PtiO2 reflects both oxygen delivery and consumption. Brain hypoxia (low brain PtiO2) has been associated with poor outcomes in patients with brain injury. Strategies to improve brain PtiO2 have focused mainly on increasing oxygen delivery either by increasing CBF or by increasing arterial oxygen content. The results of nonrandomized studies comparing brain PtiO2-guided therapy with intracranial pressure/cerebral perfusion pressure-guided therapy, while promising, have been mixed. More studies are needed including prospective, randomized controlled trials to assess the true value of this approach. The following is a review of the physiology of brain tissue oxygenation, the effect of brain hypoxia on outcome, strategies to increase oxygen delivery, and outcome studies of brain PtiO2-guided therapy in neurocritical care.

G428(P) Markers of endothelial dysfunction in newborn babies from the group of high perinatal risk

AimsTo determine the role of membrane protein, thrombomodulin, in the prediction of endothelial dysfunction in newborn babies from the group of high perinatal risk.Methods39 children from the group of a...

Efficacy of NeuroFlo Device in Treatment of Patients with Atrial Fibrillation

Atrial fibrillation (AF) is a well-established independent risk factor for stroke. We examined cerebral blood flow augmentation in the treatment of acute ischemic stroke (AIS) in patients with AF by performing secondary analysis of data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) trial, a randomized controlled trial evaluating NeuroFlo treatment in stroke patients within 14 hours of symptom onset. We report subgroup analyses of outcomes in SENTIS patients with a history or new diagnosis of AF. Among patients with AF, those treated with NeuroFlo demonstrated significant improvement over those not treated for multiple end points: global efficacy end point (P=.030), modified Rankin Scale (mRS) score 0-2 versus 3-6 (P=.029), and stroke-related mortality (P=.015). There was a significant improvement in global end point for those aged 60 years or older (P=.042) and 80 years or older (P=.017), with a trend toward improvement for age 70 years or older (P=.055), and significant improvement in those who achieved good outcomes (mRS score 0-2 versus 3-6) at age 60 years or older (P=.038), 70 years or older (P=.022), and 80 years or older (P=.008). NeuroFlo treatment in stroke patients with AF resulted in significantly better outcomes compared with nontreated patients with AF. Collateral flow recruitment, maintenance of cerebral blood flow around stroke core, and improvement of penumbral blood flow are potential mechanisms for these improved outcomes. NeuroFlo may represent a valid therapeutic option for patients with AF and AIS, and therefore, future trials of the device are warranted.

461

Introduction: Recently published guidelines for acute ischemic stroke (AIS) suggest vasopressors may be used only in exceptional cases with systemic hypotension for maintenance of cerebral blood flow. Phenylephrine (PHE) has been studied for this purpose, but the effect on clinical outcomes is unknown. Methods: In this single center, retrospective, cohort study, we identified patients who presented with AIS over a one year period from 2011–2012. Patients were excluded if they had any history of hemorrhagic stroke or any IV vasopressor use within the previous 3 days. Treatment groups were divided into those who received IV PHE titrated to maintain a blood pressure target for at least 30 minutes starting within 24 hours of hospital admission, and those who received no vasopressors (STD). The primary outcome tested was the change in stroke symptoms measured by NIH Stroke Scale (NIHSS) from baseline to hospital discharge. Secondary clinical outcomes included length of stay (LOS), in-hospital mortality, and incidence of intracerebral hemorrhage (ICH). A subgroup analysis was performed by matching cohorts with similar NIHSS at baseline. Results: Forty-five patients were included in the study (n=22 PHE vs. n=23 STD). Baseline demographics were similar between groups except for NIHSS, which was higher in the PHE group (13 PHE vs. 7 STD, p=0.044). NIHSS change from baseline to hospital discharge was not different between groups (-3 PHE vs. -2 STD, p=0.304). LOS was longer in the phenylephrine group (7 days PHE vs. 5 days STD, p=0.037). In-hospital mortality (17% PHE vs. 0%, p=0.109) and incidence of ICH (13% PHE vs. 14% STD, p=1) were similar between groups. Upon stratifying by similar baseline NIHSS to account for differences, no significant long-term clinical benefit of PHE noted at hospital discharge. Conclusions: PHE was safe, but not effective at improving outcomes in this cohort of AIS patients. This study adds strength to the evidence that blood pressure augmentation with vasopressors should not be routinely applied to AIS patients.

Nitric oxide: Roles in neurovascular regulation and ischemic brain injury

The brain relies on a continuous delivery of energy substrates through the blood supply, and interruption of cerebral blood flow (CBF) leads to brain damage. Nitric oxide (NO) has been implicated both in the regulation of the cerebral microcirculation and in ischemic brain injury. In the normal brain, neuronal NO is involved in the CBF increases produced by synaptic activity, a vital response that matches CBF delivery to brain activity. The mechanisms of the NO production induced by neural activity involve the NMDA receptor, a subunit of which is tethered to neuronal NO synthase (nNOS) via the adaptor protein PSD-95. The ability of NMDA receptors to trigger NO production depends on tissue plasminogen activator (tPA), which promotes NO production through nNOS phosphorylation. NO is also involved in ischemic brain injury. NO produced by endothelial NOS (eNOS) is protective in the early stages after the arterial occlusion by promoting the maintenance of CBF in brain regions at risk for infarction (ischemic penumbra). However, in the late stages of cerebral ischemia large amounts of NO produced by the “inducible” isoform of NOS (iNOS) in inflammatory cells infiltrating the ischemic tissue is deleterious and contributes to brain injury. Post-ischemic iNOS expression is controlled by the transcription factor NFkb, which is activated through CD36, a scavenger receptor involved in innate immunity. Thus, enhancement of eNOS-derived NO and suppression iNOS-derived NO may have translational potential in cerebrovascular pathologies.

Blood Pressure Lowering with Valsartan Is Associated with Maintenance of Cerebral Blood Flow and Cerebral Perfusion Reserve in Hypertensive Patients with Cerebral Small Vessel Disease

The purpose of this study was to determine the effect of systemic blood pressure-lowering treatment with an angiotensin II receptor blocker, valsartan, on cerebral hemodynamics in patients with hypertension and evidence of cerebral small vessel disease. We used positron emission tomography and acetazolamide challenge tests to measure cerebral blood flow (CBF) and cerebrovascular reserve (CVR) in 8 patients with hypertension (mean age 70.8 years) with lacunar infarcts and white matter lesions before and after valsartan therapy. Systemic blood pressure was significantly decreased from baseline after treatment with valsartan. The baseline global CBFs before and after treatment were 38.2 +/- 5.6 mL/min/100 g and 39.9 +/- 9.0 mL/min/100 g, respectively. The CVRs before and after treatment were 52.2 +/- 18.4% and 39.7 +/- 18.9%, respectively. Differences in these parameters were not significant. Both regional CBF and CVR in the corona radiata with moderate or severe white matter lesions were also preserved after valsartan therapy compared with those before treatment. Cerebral hemodynamics were preserved after blood pressure lowering with valsartan therapy. Valsartan could be a feasible antihypertensive regimen in terms of cerebral circulation in patients with cerebral small vessel disease.

Influence of Changes in Blood Pressure on Cerebral Perfusion and Oxygenation

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of "normal" CA has not been clearly identified. While controlling for the influence of arterial Pco(2), we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal Pco(2), and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: approximately 40 to approximately 125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv(mean) was altered by 0.82+/-0.35% per millimeter of mercury change in mean blood pressure (R(2)=0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=-0.18%/mm Hg; R(2)=0.60) and MCAv(mean) (slope=-0.26%/cm . s(-1); R(2)=0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv(mean).

Hemodynamic and Histological Effects of Traumatic Brain Injury in eNOS-Deficient Mice

Microvascular dysfunction in the brain, characterized by vasoconstriction, vascular occlusion, and disruption of the blood brain barrier, may adversely affect outcome following traumatic brain injury (TBI). Because of its vasodilating and antiaggregative properties, nitric oxide (NO) produced by nitric oxide synthase in the endothelium (eNOS) is a key regulator of vascular homeostasis. The objective of the present study was to evaluate the role of eNOS in vascular disturbances and histological outcome in the brain following TBI. Cortical blood flow ([(14)C]-iodoantipyrine technique), number of perfused capillaries (FITC-dextran technique), brain water content (wet vs. dry weight), and the transfer constant (K(i)) for [(51)Cr]-EDTA, reflecting permeability, were analyzed 3 h and 24 h after a controlled cortical impact injury (CCI) in eNOS-deficient (eNOS-KO) and wild-type (WT) mice. Cortical contusion volume and cell count in the hippocampus were evaluated 3 weeks after injury. Blood flow in the injured cortex decreased in both groups following trauma. There were no significant differences between the groups at 3 h, but blood flow was lower in eNOS-KO mice than in WT mice 24 h after trauma. Brain water content was higher in the WT mice than in eNOS-KO mice at 24 h. Number of perfused capillaries, K(i), and histological outcome were similar in both groups. We conclude that eNOS is important for maintenance of cerebral blood flow after trauma and that eNOS promotes edema formation by mechanisms other than increased permeability. The vascular effects of eNOS do not, however, influence histological outcome.