Cerebrovascular reactivity following administration of mirtazapine in healthy probands--a randomized, placebo controlled double-blind clinical study

INTRODUCTION: Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is important for maintaining constant cerebral blood flow. A reduced CVR increases the risk of stroke. We recently found that CVR was reduced in patients with depression. This might contribute to the higher risk of stroke that has been found in subjects suffering from depression. The characterization of pathophysiological conditions in the cerebral circulation requires the knowledge of influencing factors on CVR. We therefore investigated the influence that antidepressant administration might have on CVR in humans. METHODS: We investigated CVR in 48 healthy men before and after a 10-day application of either mirtazapine or placebo. CVR was determined by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial Doppler ultrasound. RESULTS: There was no significant group-difference of CVR after the treatment trial compared to baseline. DISCUSSION: Mirtazapine does not seem to have an influence on CVR, or any impact on CVR might have been quickly limited by a cerebral autoregulatory response.     

Cerebrovascular reactivity in depressed patients without vascular risk factors

INTRODUCTION: Cerebrovascular reactivity (CVR) seems to be gaining importance as a prognostic factor for stroke risk. CVR reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus; this mechanism plays an important role in maintaining a constant cerebral blood flow. Evaluating factors that influence CVR will help prevention or early detection of cerebrovascular disease (CVD). In this study we aimed to measure the CVR in vascular-risk free depressed individuals so as to evaluate the effect depression has on CVR and hence its role as a stroke risk factor. METHODS: Using acetazolamid (ACZ) stimulation, CVR was assessed with a transcranial Doppler ultrasound in 25 non-smoking depressed patients (average age: 48.48 +/- 14.40) and in 25 healthy non-smoking controls (average age: 46.76 +/- 13.69) by calculating the difference between the maximal mean blood flow velocity at baseline and the maximal mean blood flow velocity after ACZ stimulation. RESULTS: Basal Cerebral Blood flow in Patients was 50.6 cm/s (SD: 11.6) versus controls 52.80 cm/s (SD: 12.70) whereas after stimulation maximal blood flow velocity was 72.64 cm/s (SD: 15.75) in patients versus 80.20 cm/s (SD: 18.43) in controls. In an analysis of covariance we found that cerebrovascular reactivity was significantly reduced in the vascular-risk free depressed sample. Age had a significant influence whereas gender did not. DISCUSSION: Major Depression appears to decrease cerebrovascular reactivity supporting the idea of increased risk for stroke in depressed patients. The mechanisms leading to this phenomenon and its subtle subgroup differences should be further investigated.     

Cerebrovascular reactivity over time-course - From major depressive episode to remission

Introduction

Depression is a prospective risk factor for stroke. Little is known, however, about the pathophysiologic links leading to this association. Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is an important mechanism to provide constant cerebral blood flow. In the absence of major arterial stenosis, an impaired CVR has been associated with a higher risk of stroke. We hypothesized that CVR might be continuously reduced in patients with major depression even after successful remission thus contributing to the association between depression and stroke.

Materials and methods

We investigated CVR in a group of patients (N = 29) in the acute episode of depressive illness and after 21 months under euthymic condition. A healthy control group (N = 33) was investigated at comparable time intervals. All patients and controls were otherwise healthy. CVR was investigated by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial doppler ultrasound.

Results

A group of acutely depressed patients presented a significantly reduced CVR compared to controls. On follow-up 21 months later after treatment and remission, CVR in the patient group had significantly improved, whereas CVR in the control group remained unchanged. Confounding factors had no significant influence.

Discussion

CVR is impaired during major depression. Since CVR seems to improve after treatment of depression, the contribution to an increased stroke risk among depressive patients may be true for a subgroup only and needs to be further investigated.     

Cerebrovascular reactivity during the Valsalva maneuver in migraine, tension-type headache and medication overuse headache

The aim of this study was to investigate, by means of transcranial Doppler ultrasound (TCD), cerebrovascular reactivity during the Valsalva maneuver (VM) during the headache-free interval in patients with migraine (M), migraine plus tension-type headache (M+TTH), and migraine plus medication overuse headache (M+MOH). A total of 114 patients (n=60 M, n=38 M+TTH, n=16 M+MOH) and n=60 controls were investigated; diagnoses were made according to the International Headache Society criteria. All subjects underwent TCD monitoring and, simultaneously, non-invasive assessment of arterial blood pressure and end-tidal CO2. Two indices were determined: the cerebrovascular Valsalva ratio (CVR) was calculated as the maximum end-diastolic flow velocity acceleration during the late straining phase of the VM [cm/s2] and the centroperipheral Valsalva ratio (CPVR) was defined as the quotient of CVR to the concomitant arterial blood pressure acceleration [cm/mmHg x s]. The dynamic cerebrovascular autoregulatory response to the VM, measured as CVR, was increased in patients with M and M+TTH compared to age-matched healthy subjects. By contrast, CPVR (i.e. the quotient of the cerebrovascular to the peripheral autonomic response), was increased in M patients compared to healthy subjects and all other headache conditions tested. Cerebrovascular autoregulatory response during the VM was increased in M patients compared to age-matched normal healthy subjects, indicating a disturbed autonomic control of cerebral vasoreactivity. The CPVR seems to be a sensitive parameter for distinguishing between M patients and M+TTH or M+MOH patients.     

Impairment of cerebral hemodynamic response to the cold pressor test in patients with Parkinson's disease

Background and purposeDisturbance of the autonomic nervous system (ANS) is frequently encountered in Parkinson's disease (PD). In this study, we examined changes in systemic and cerebral hemodynamics during the cold pressor test (CPT) to determine whether cerebrovascular reactivity, controlled by the sympathetic nervous system, is intact or impaired in patients with PD.MethodsForty-nine patients with PD and 49 sex- and age-matched non-PD subjects were evaluated. Measurements were performed in the resting state and over a period of 1 min of CPT. The cerebral blood flow velocity (CBFV) and pulsatility index (PI) of the middle cerebral artery (MCA) were recorded by transcranial color-coded Doppler ultrasonography (TCCS). Mean arterial blood pressure (MAP), heart rate (HR), and end-tidal CO₂ (Et-CO₂) were investigated simultaneously. The resistance of the cerebrovascular bed (CVR) was calculated as the ratio of mean arterial blood pressure to mean cerebral blood flow velocity (Vm). Changes of Vm, PI and CVR in response to the cold pressor test were evaluated.ResultsBaseline values for control and PD subjects showed no statistical difference. CPT induced a significant increase in MAP, HR, and Vm in both groups. Pulsatility index (PI) and CVR were decreased in both groups during CPT. Percent increases of Vm (P < 0.001) and MAP (P = 0.011) were significantly higher while the percent decreases of PI (P = 0.002) and CVR (P = 0.007) were significantly decreased more in the non-PD group.ConclusionsThis study indirectly shows that ANS-mediated cerebrovascular reactivity is impaired in patients with PD. Further investigations are needed to confirm the hypothesis that using the cold pressor test to evaluate cerebrovascular reactivity might be beneficial in early diagnosis of impairment of ANS-mediated cerebrovascular autoregulation in patients with PD.     

A transcranial Doppler study of basilar hemodynamics in progressive carotid artery disease

Abstract

In carotid artery disease (CAD) the basilar artery (BA) may act as an important intracranial collateral to supply hypoperfused middle cerebral artery (MCA) territories. Transcranial Doppler studies were performed to study the dependency between BA hemodynamics in relation to the MCA perfusion status. BA and MCA blood flow velocities (BFV), pulsatility indices (API) and cerebrovascular reactivity (CVR) were assessed in 40 patients with a progressive MCA hypoperfusion due to progressive CAD. All patients had patent cervical segments of their vertebral arteries with an antegrade vertebral flow profile. Duplex studies were performed to diagnose the severi~ of CAD. Hypoperfusion of the MCA was diagnosed by the degree of vasoparalysi assessed by a Diamox procedure. Analysis showed that the basilar BFV significantly increased in cases of progressive CAD; the basilar PI decreased but the basilar CVR remained unchanged. However, in cases of bilateral hemodynamic significant CAD and bilateral exhausted CVR in the MCA territory, the basilar artery did not exhibit an increase of BFVs or a decrease of the basilar PI, but the basilar CVR showed a significant decrease. Basilar artery CVR is not impaired if this artery has a function as intracranial collateral in CAD. However in cases of bilateral hypoperfused MeA territories the basilar artery does not function as a collateral pathway. The basilar CVR declines under these circumstances which merely reflects the exhausted hemodynamics in the anterior/posterior borderzones. This situation might lead to an increased stroke risk in the distal basilar supply zones. [Neural Res 1998; 20: 493-498]     

Evaluation of cross-circulation through circle of Willis using an ultrasonic Doppler technique. Part II. Comparison between blood flow velocity by ultrasonic Doppler flowmetry and cerebrovascular resistance

The correlation between the increase in velocity of blood flow in both the internal carotid and vertebral arteries during a carotid compression and the cerebrovascular resistance (CVR) was investigated in 11 patients with chronic ischemic cerebrovascular disease and 4 without organic brain lesions. The velocity of blood flow was measured by an ultrasonic Doppler flowmeter. CVR was calculated from cerebral blood flow and arterial blood pressure. There was no correlation between the increased velocity of blood flow in the internal carotid and vertebral arteries and CVR. The increased velocity of blood flow in patients with low CVR was, however, significantly higher than that of patients with high CVR. The investigation of cross-circulation by ultrasonic Doppler flowmetry is a useful non-invasive method for the detection of changes in cerebral vascular resistance.     

Compromised cerebrovascular modulation in chronic anxiety: evidence from cerebral blood flow velocity measured by transcranial Doppler sonography

Objective Cerebral autoregulation(CA) is the mechanism by which constant cerebral blood flow is maintained despite changes in cerebral perfusion pressure.CA can be evaluated by dynamic monitoring of cerebral blood flow velocity(CBFV) with transcranial Doppler sonography(TCD).The present study aimed to explore CA in chronic anxiety.Methods Subjects with Hamilton anxiety scale scores≥14 were enrolled and the dynamic changes of CBFV in response to an orthostatic challenge were investigated using TCD.Results In both the anxious and the healthy subjects,the mean CBFV was significantly lower in the upright position than when supine.However,the CBFV changes from supine to upright differed between the anxious and the healthy groups.Anxious subjects showed more pronounced decreases in CBFV with abrupt standing.Conclusion Our results indicate that cerebrovascular modulation is compromised in chronic anxiety;anxious subjects have some insufficiency in maintaining cerebral perfusion after postural change.Given the fact that anxiety and impaired CA are associated with cardiovascular disease,early ascertainment of compromised cerebrovascular modulation using TCD might suggest interventional therapies in the anxious population, and improve the primary prevention of cardiovascular disease.     

Regional cerebral blood flow in lacunar infarction.

Ten cases of lacunar infarction, 10 cases of nonlacunar cerebral thrombosis, and 8 healthy controls who did not have risk factors of cerebrovascular diseases were studied. Subcortical cystic infarctions with a diameter of less than 1.5 cm were classified as lacunar infarction and the other cerebral thrombosis were classified as nonlacunar cerebral thrombosis. Cerebral blood flow examination by Xenon computed tomography (CT) method was performed within 14 days after the onset of stroke. Stable Xenon was inhaled for 3 minutes and CT scan was taken once before the inhalation, 3 times during the inhalation, and 5 times in the washout phase. Regional blood flows in the infarcted area, around the infarcted area, and in the cerebral cortex and the cerebral white matter where the influence of the infarction was considered to be little were measured before and after intravenous injection of 17 mg/kg acetazolamide. In the lacunar infarction, the blood flow in the cerebral cortex where the influence of the infarction was considered to be little was decreased and the cerebrovascular dilatory reserve capacity in the cerebral cortex and the cerebral white matter was decreased. Arteriolosclerosis is considered to be the basic cause of lacunar infarction.     

Effect of ammonia intoxication on cerebral blood flow, its autoregulation and responsiveness to carbon dioxide and papaverine.

Cerebral blood flow (CBF) was measured in anaesthetised cats with 133Xe clearance method under normal conditions and with hyperammonaemia. Elevation of blood ammonia concentration by an intravenous infusion of ammonium acetate caused an increase in CBF and a parallel decrease in cerebrovascular resistance (CVR). These parameters reached, however, plateau at an arterial blood ammonia level exceeding 500 mumol/l. Cerebrovascular reactivity to CO2 diminished following elevation of blood ammonia concentration and at arterial blood ammonia level exceeding 500 mumol/l it was virtually abolished. In contrast, hyperammonaemia influenced neither cerebrovascular responsiveness to papaverine nor autoregulatory properties of the cerebral circulation. It is concluded, therefore, that hyperammonaemia exerts some dilatatory effect on cerebral vessels and severely impairs chemical regulation of CBF but does not elicit cerebral vasomotor paralysis.     

阿尔兹海默病与皮质下型血管性痴呆患者脑血管反应性的比较研究

目的了解阿尔兹海默病（AD）相对于皮质下型血管性痴呆患者（SVD）脑血管反应性（CVR）的变化特征及规律。方法应用动脉自旋标记核磁共振技术（ASL）首先定量测定静息状态下两组病例局部脑血流量（rCBF）,然后分别吸入5％的C02各1min,再次测定rCBF,并计算其增加率以代表CVR。结果相比SVD组,AD组在双侧额叶皮质有显著性的CVR下降。结论AD在双侧额叶皮质CVR的下降可能是鉴别于SVD的一个重要临床客观指标。     

Cerebral blood flow regulation during cognitive tasks: effects of healthy aging

Aging is associated with frontal subcortical microangiopathy and executive cognitive dysfunction, suggesting that elderly individuals may have impaired metabolic activation of cerebral blood flow to the frontal lobes. We used transcranial Doppler (TCD) ultrasound to examine the cerebral blood flow response to executive control and visual tasks in the anterior and posterior cerebral circulations and to determine the effects of healthy aging on cerebral blood flow regulation during cognitive tasks. Continuous simultaneous anterior cerebral artery (ACA) and posterior cerebral artery (PCA) blood flow velocities (BFVs) and mean arterial pressure (MAP) were measured in response to word stem completion (WSC) and a visual search (VS) task in 29 healthy subjects (14 young, 30+/-1.5 years; 15 old, 74+/-1.4 years). We found that: (1) ACA and PCA blood flow velocities are both significantly increased during WSC and VS cognitive tasks, (2) ACA and PCA activations were task specific in our young volunteers, with ACA>PCA BFV during the WSC task and PCA>ACA BFV during the VS task, (3) while healthy elderly subjects also had PCA>ACA BFV during the VS task, they did not have ACA>PCA activation during the WSC task, and (4) healthy elderly subjects tend to have overall greater increases in BFV during both cognitive tasks. We conclude that TCD can be used to monitor cerebrovascular hemodynamics during the performance of cognitive tasks. Our data suggest that there is differential blood flow increase in the ACA and PCA in young versus elderly subjects during cognitive tasks.     

Orthostasis as a test for cerebral autoregulation in normal persons and patients with carotid artery disease.

Orthostasis reduces mean flow velocity (FVmean) in cerebral arteries. This might be used as an alternative provocation test for cerebral hemodynamics in patients with carotid artery disease (CAD). In 21 unilateral CAD patients and 21 controls, FVmean in both middle cerebral arteries (MCA) was measured by transcranial Doppler, together with blood pressure (BP) and heart rate (HR) during a tilt table test. Cerebrovascular reserve (CVR) was measured by an acetazolamide test. In all cases, FVmean dropped to a lower level (controls: 81.9 +/- 9.4% of baseline; patients: 84.3 +/- 7.9% symptomatic side, 85.6 +/- 9.0% contralateral). Impaired CVR patients showed a smaller (p < 0.01) decrease (90.6 +/- 3.3%) compared to contralateral (84.9 +/- 6.0%), to normal CVR patients (81.1 +/- 7.8%) and to controls. Heart rate increased in both groups (controls: +16.6 +/- 9.9%, patients +10.3 +/- 9.9%; p < 0.01); BP showed no change. Orthostasis induces a decrease of MCA FVmean as already previously described. This decrease is significantly smaller in patients with impaired CVR. Since BP does not change, some authors explain the lower MCA Fvmean during orthostasis as caused by sympathetic induced vasoconstriction of cerebral resistance vessels. The authors speculate that in impaired CVR-patients autoregulative protection against ischemia might limit vasoconstriction. In combination with standard tests for measurement of CVR, this test might be useful for evaluation of cerebral autoregulation.     

Middle cerebral artery blood flow velocity, end-tidal pCO2 and blood pressure in patients with obstructive sleep apnea and in healthy subjects during continuous positive airway pressure breathing

There is conflicting evidence in the literature as to the potential effect of continuous positive airway pressure (CPAP) on cerebral perfusion. Compromising cerebral perfusion could possibly outweigh the benefit of improved oxygenation. Patients with the obstructive sleep apnea syndrome (OSAS) have been claimed to have a higher cerebrovascular reactivity to changes in end-tidal pCO2. In this study, we investigated 23 patients with OSAS and 16 healthy young adults in the waking state. Both groups performed a series of 10 min of normal breathing, 20 min with 9 cmH2O nasal CPAP, and then 10 min of normal breathing while wearing a nasal CPAP mask. The following parameters were assessed: bilateral transcranial Doppler signal of the middle cerebral artery, systolic and diastolic blood pressure assessed manually, and cerebrovascular reactivity to changes in pCO2 during hyperventilation and rebreathing into an airbag. Continuous end-tidal pCO2 measurements were performed in 14 subjects. As compared with normal breathing middle cerebral artery blood flow velocity and pCO2 remained unchanged during CPAP. Systolic and diastolic blood pressure increased slightly by 1.2 mmHg (p = 0.015) and 1.1 mmHg (p = 0.007), respectively. Cerebrovascular reactivity did not differ in the two groups. Nasal CPAP of 9 cmH2O is a safe treatment with respect to the maintenance of cerebral blood flow. Our study gives further evidence for the autoregulation's capacity to maintain cerebral blood flow velocity constant during different levels of intrathoracic pressure and different cerebral perfusion pressures. We could not demonstrate any difference in cerebrovascular reactivity between patients with OSAS and healthy persons.     

The dose-response relationship of acetazolamide on the cerebral blood flow in normal subjects

BACKGROUND: Acetazolamide (AA) is used to determine the cerebral vasoreactivity (CVR). To investigate whether the usually applied standard dose of 1 g intravenously will guarantee stable test conditions, the dose-response relationship of AA on cerebral blood flow (CBF) and cerebral blood flow velocity (CBFV) in normal subjects was determined. METHODS: In 59 healthy volunteers, rCBF was measured with a (133)Xenon inhalation device, and CBFV of the middle cerebral artery (MCA) by transcranial Doppler sonography. The first CBF measurement was taken at rest, the second 15 min after application of AA at a dosage of 5, 10, 13, 15 and 18 mg/kg of body weight, respectively. The CBFV (n = 52) of the middle cerebral artery on the side of the better temporal window was taken 25 min after application of AA 13 mg/kg. In order to determine the side effects of AA, statements of an additional 172 patients were included. RESULTS: A significant dosage dependence of AA on the CBF (fast flow and initial slope index) exists between 5 and 18 mg/kg intravenously. After AA 13 mg/kg, the fast flow increases from 70.8 +/- 10.8 to 110.1 +/- 13.5 ml/100 g/min, the initial slope index from 46.5 +/- 5.4 to 62.8 +/- 5.8, and the CBFV from 51.5 +/- 8.5 to 85.4 +/- 14.2 cm/s. The CVR of CBF and CBFV ascertained that way shows an age dependence equivalent to the situation at rest. Severity and frequency of side effects are dosage-dependent, significantly in part, but reversible without exception. CONCLUSION: For the determination of CVR of CBF with AA, a dosage related to body weight is required. The usually applied standard dose of 1 g intravenously is not sufficient for standardized test conditions. For evaluation of the results obtained, the apparent age dependence of CVR must be taken into account. Because of the severity of side effects occurring at a higher dose, an AA dosage of 13 mg/kg intravenously is recommended.     

急进高原的健康人群脑血管反应性研究

【摘要】
目的 探讨健康成年人急进高原低压、低氧环境后脑血管反应性（cerebrovascular reactivity,CVR）的变化及其可能机制。
方法 采用经颅多普勒超声监测仪评估健康成年人从海拔2200 m急进到海拔3800 m前后CVR;用硝酸还原酶法测定该组研究人群血浆一氧化氮（nitric oxide,NO）水平,采用酶联免疫吸附法测定其血浆内皮型一氧化氮合酶（endothelial nitric oxide synthase,eNOs）水平。
结果 研究人群共46例,急进高原后较急进高原前CVR增高,差异有显著性［CVR：2.36±0.74 vs 1.43±0.46,P<0.001;CVR指数（cerebrovascular reserve index,CVRI）：2.56 0.89 vs 1.82 0.71,P<0.001］;血浆NO水平升高,差异有显著性［（44.97± 0.68）μmol/L vs（34.45± 2.86）μmol/L,P<0.001］;血浆eNOS水平升高,差异有显著性［（274.81±13.68）pg/ml vs （209.73±14.34）pg/ml,P<0.001］;急进高原后较急进高原前正常呼吸时双侧大脑中动脉平均脑血流速度明显升高,差异有显著性［（93.78±11.67）cm/s vs （80.85±11.14）cm/s,P<0.001］。
结论 健康成年人急进高原后,CVR、血浆NO及eNOS含量和大脑中动脉平均脑血流速度都明显升高,以适应急进海拔3800 m后的脑缺氧情况。     

Phase-Contrast Magnetic Resonance Angiography for the Determination of Cerebrovascular Reserve

Cerebrovascular reserve (CVR) is the potential for cerebral arteriolar dilatation to occur, in response to decreased cerebral perfusion pressure, in order to maintain constant cerebral blood flow. Diminution or absence of CVR is considered a risk factor for stroke. Current methods for determining CVR include singlephoton emission computed tomography, positron emission tomography and transcranial Doppler (TCD) ultrasonography. However, significant advantages could derive from the utilization of magnetic resonance angiography (MRA) based on the concurrent acquisition of hemodynamic information (CVR and collateral flow) with phase?contrast (PC) techniques and vascular morphology with three?dimensional, time?of?flight methods. With a 1.5?T scanner and acetazolamide (AZM), an arteriolar dilator, CVR was determined in 7 normal subjects. Mean flow velocity in the middle cerebral arteries was determined by PC MRA before and after AZM administration. For comparative purposes, mean flow velocities in the same middle cerebral arteries were determined by TCD before and after AZM administration. The mean flow velocities were as follows (mean ± standard deviation, n = 7): 40 ± 8 (PC MRA) versus 61 ±10 cm/sec (TCD) before AZM treatment and 58 ±11 (PC MRA) versus 85 ±15 cm/sec (TCD) after AZM administration. The increase in mean flow velocity (before vs after AZM), that is, the CVR, was 45 ±11 % as shown by PC MRA and 39 ± 14% as shown by TCD. Although significant differences were present between the mean flow velocities measured before and those after AZM administration, as determined by PC MRA and TCD, the CVR was not significantly different (45 vs 39%, respectively). These preliminary results suggest that PC MRA may be a method for determining CVR.     

Evaluation of blood flow velocity and cerebrovascular reactivity in patient with posterior circulation stroke

The aim of our study was to determine the type of blood flow disturbances and cerebrovascular reactivity of major anterior and posterior circulation cerebral vessels in patients with posterior stroke (POCI). The examined group consisted of 17 patients, mean age 57 +/- 12 yr, with posterior circulation infarct. Neurological examination, brain CT and Doppler examination including evaluation of BFV and CVR of MCA, PCA and VA was performed in each patient. Doppler examination was done using Pioneer TC 2020 and capnograph Tidal Wave sp Novametrix. RESULTS: BFV of ICA's, MCA's, ACA's and PCA's were diminished while BFV of VA's were significantly diminished in the examined patients compared to healthy controls. CVR of MCA in posterior circulation stroke patients was significantly lower compared to controls. CVR of PCA and VA was significantly lower compared to CVR of MCA in patients with posterior circulation stroke. CONCLUSION: Impairment of CVR, especially in posterior circulation, plays an important role in posterior circulation stroke pathogenesis.     

Relative cerebral ischemia in SHR due to hypotensive hemorrhage: cerebral function, blood flow and extracellular levels of lactate and purine catabolites

Cerebral blood flow (CBF, by laser Doppler flowmetry) and extracellular cortical concentrations (by microdialysis) of adenosine, inosine, xanthine, hypoxanthine, and lactate were measured together with somatosensory evoked potentials (SEP) in chloralose-anaesthetized spontaneously hypertensive rats (SHR) during relative cerebral ischemia induced by hypotensive hemorrhage. Reduction of mean arterial blood pressure (MABP) to 40-50 mm Hg, which decreased SEP to about 50% of prebleeding control level, decreased CBF only to about 75% of control due to cerebrovascular "autoregulation." A secondary, marked rise in cerebrovascular resistance (CVR) occurred after about 15 min in parallel with a striking increase in heart rate (after initial bradycardia). This late rise in heart rate is probably elicited by relative ischemia in medullary centers. The increase in CVR might indicate increased sympathetic nerve activity to the circle of Willis and large cerebral arteries. Cortical lactate increased initially but started to decline after about 30 min, and after 2 h it was not significantly higher than control. Cortical adenosine, inosine, hypoxanthine, and xanthine increased slowly and were significantly elevated after 50 min of hemorrhage. After 80 min, adenosine and inosine had returned to initial levels, while hypoxanthine and xanthine were further elevated. Despite the apparent partial recovery of metabolic disturbances during late hemorrhage, and with a blood flow maintained at 75% of resting control, SEP did not improve. It is suggested that the depression of SEP is not primarily caused by circulatory-metabolic derangements, but instead by activation of specific inhibitory systems.     

Hemorrhage-induced cerebral vasoconstriction in dogs

Cerebrovascular responses to a 20% volume hemorrhage were studied in chloralose-anesthetized dogs with the Doppler cerebral venous outflow method. Arterial PCO2, PO2, and pH were held constant by servocontrol of ventilation. The experimental results were divided into 2 groups as determined by the spontaneous responses of mean arterial pressure (MAP) to hemorrhage. In Group 1 (n = 11), steady state MAP decreased 25%, cerebral blood flow (CBF) decreased 15%, and cerebrovascular resistance (CVR) decreased 13% (autoregulatory vasodilatation). In group 2 (n = 23), MAP changed less than 10 mm Hg, CBF decreased 13%, and CVR increased 15%. The hemorrhage-induced cerebral vasoconstriction in Group 2 was characterized by the following: phenoxybenzamine (2 mg/kg i.v., n = 3) reduced post-hemorrhage CVR from 116% to 95% of prehemorrhage CVR (cCVR); phentolamine (2 mg/kg i.v., n = 5) reduced post-hemorrhage CVR from 114% to 91% of cCVR; and verified local anesthetization of both superior cervical ganglia (n = 5) reduced post-hemorrhage CVR from 116% to 94% of cCVR. Thus in Group 2, sympathetic vasoconstriction contributed approximately 5% of cCVR; following normotensive hemorrhage, it accounted for up to 20% of post-hemorrhage CVR. In combination with prevous studies, these data suggest that cerebrovascular responses to hemorrhage balance between autoregulatory vasodilatation and sympathetic vasoconstriction.