Effects of endothelin on blood vessels of the brain and choroid plexus

Endothelin is a recently described vasoactive peptide produced by endothelial cells. Receptors for endothelin are found throughout the brain, and are particularly dense in the choroid plexus. Effects of endothelin on cerebral blood flow and blood flow to the choroid plexus are not known. In this study, we examined effects of endothelin (100 and 1000 ng/kg i.v.) on regional blood flow (microspheres) and cerebral microvascular pressure in anesthetized rabbits. Endothelin (1000 ng/kg) produced only a 4 +/- 2 mm Hg (mean +/- S.E.M.) increase in systemic blood pressure, and had no effect on cerebral blood flow or cerebral microvascular pressure. In contrast, endothelin produced a marked decrease in blood flow to the choroid plexus and dura mater. Blood flow to choroid and dura remained significantly decreased 1 h after administration of the peptide. Endothelin also reduced blood flow to the kidney and small intestine, but the decreases tended to be less than in choroid plexus or dura mater. Thus, circulating endothelin, at doses that have no effect on cerebral blood vessels, has marked effects on blood flow to the choroid plexus. These findings suggest that circulating or locally produced endothelin may contribute to regulation of brain fluid balance through effects on choroid plexus and production of cerebrospinal fluid.     

Endothelin-1 and cerebral blood flow in a porcine model.

The purpose of the study was to investigate whether provoked changes of cerebral perfusion pressure and arterial carbon dioxide tension are able to influence the cerebral metabolism of endothelin-1 (ET-1) in a porcine model. Brain tissue oxygen tension, regional cerebral blood flow and mean arterial blood pressure were monitored in 10 healthy pigs during induced hyperventilation (HV), hypertension (HrT) and hypotension (HoT). ET-1 was determined in the arterial and cerebrovenous blood. Microdialysis samples (lactate, glucose and pyruvate) were taken from brain and subcutaneous tissue. A significant decrease (p<0.05) of the arterial ET-1 (1.46+/-0.33 fmol/mL) compared to the baseline (2.18+/-0.36 fmol/mL) was observed after the HoT-period. We detected a positive correlation between cerebrovenous ET-1 and extracellular cerebral glucose (0.68; p<0.05) after the baseline as well as a negative correlation of -0.81 (p<0.005) between the cerebrovenous ET-1 level and the extracellular cerebral lactate after the HoT-period. These data imply that with increasingly pathological changes of the cerebral metabolism endothelin becomes progressively more important in the regulation of cerebral vascular tone.     

Effect of a new vasodilator (flunarizine) on the cerebral circulation.

In order to clarify the effects of flunarizine, a newly-synthesized derivative of piperazine on cerebral circulation and metabolism, cerebrocortical oxygen tension, carbon dioxide tension and cerebrocortical blood flow were continuously recorded, along with a simultaneous monitoring of arterial blood pressure in 11 cats. Maximal changes in cerebrocortical oxygen tension induced by intravenous administration of flunarizine (0.6-1.0 mg/kg) were compared with those of papaverine hydrochloride (1 mg/kg). Flunarizine caused increases in cerebrocortical oxygen tension as well as cerebrocortical blood flow and a decrease in cerebrocortical carbon dioxide tension despite a fall in blood pressure, indicating an increase of cerebral blood flow presumably due to cerebral vasodilatation. Since the increase of cerebrocortical oxygen tension induced by flunarizine was comparable to that induced by papaverine, it was concluded that flunarizine appears to be a potent vasodilator of cerebral vessels.     

Effects of carbon dioxide inhalation on cerebral blood flow and oxygen tissue level in spontaneously hypertensive rabbits.

BACKGROUND AND PURPOSE: Because previous studies have yielded conflicting results, this study was designed to investigate the efficiency of cerebrovascular reactivity to carbon dioxide in hypertension associated with moderate diffuse cerebral ischemic lesions. METHODS: The effects of carbon dioxide inhalation on mean arterial blood pressure, heart and respiration rates, cerebral cortical blood flow, polarographically detected oxygen currents (oxygen availability), and cerebral electrical activity were compared in 14 spontaneously hypertensive and 16 normotensive rabbits anesthetized with urethane and alpha-chloralose. Blood flow was measured with the hydrogen clearance and thermal clearance methods. RESULTS: In the resting state the frequency of electrical activity shifted to slower components, the levels of oxygen availability and cerebral blood flow were lower (p less than 0.01), and the ratio of the two latter parameters was greater (p less than 0.01) in hypertensive rabbits than in normotensive animals. Carbon dioxide inhalation induced more marked increases in cerebral blood flow, respiration rate, and oxygen availability in hypertensive (p less than 0.01) than in normotensive (p less than 0.05) rabbits. The ratio of oxygen availability to cerebral blood flow decreased (p less than 0.01) in the former and did not change significantly in the latter group. The carbon dioxide-induced rise in blood flow was also slower and more protracted in hypertensive rabbits (p less than 0.01). Histological investigation revealed groups of neurons with ischemic changes in the cortex of the hypertensive rabbits. CONCLUSIONS: We suggest that in hypertensive rabbits the mild multiple ischemic lesions are the basis of functional disturbances, including reduced resting cerebral blood flow, greater oxygen tissue level, slower response to carbon dioxide, and greater vasodilatory capacity.     

Cerebral microvessel endothelium is producing endothelin

Endothelin, a potent vasoconstrictor peptide, was recently isolated from the supernatant of the cultured endothelia of the porcine aorta and is now supposed to be the most likely candidate for the endothelium-derived contractile factor (EDCF), which is responsible for the endothelium-dependent vasoconstriction by various stimuli. In this study, the production of endothelin by the endothelia of porcine cerebral microvessels was revealed by the Northern blot analysis with porcine endothelin cDNA probe and the enzyme-linked immunosorbent assay (ELISA) with anti-porcine endothelin antibody. Our results raise the possibility that the endothelia of cerebral microvessels regulate the local blood flow within the brain through the production of endothelin.     

Influence of superior cervical ganglion on cerebral hemodynamics--measurements of cerebral blood flow and metabolism during superior cervical ganglionectomy in patients with moyamoya disease

The effect of superior cervical ganglionectomy (SCG) on cerebral blood flow and metabolism was investigated in moyamoya disease. Measurement of cerebral blood flow and metabolism was performed in 12 cases (15 operations) of moyamoya disease during SCG. Mean age was 65.2 years (from 3 to 38). 4 were male and eight were female. Ischemic cases were 8 and hemorrhagic cases were 4. At encephalo-duro-anterio-synangiosis, a Laser Doppler flow meter and probes for measuring cortical tissue oxygen and carbon dioxide were set out to allow measurement from identical sites on the surface of the brain over the cortex. Moreover, an electromagnetic flow meter was placed on the common carotid artery. And the mean arterial blood pressure was also measured from femoral artery. After the electrode had been stabilized, continuous recordings were made of cerebral blood flow and metabolism during SCG. The mean arterial blood pressure fell slightly post operatively, but the changes in blood pressure were considered not to be significant enough to affect blood flow. Cortical CBF did not change immediately after SCG. However it increased gradually to 118.8% of preoperation level 30 minutes later respectively, and the difference was observed significant. The carotid blood flow and the tissue oxygen developed a tendency to increase after 30 minutes, but the tissue carbon dioxide did not changed. The present study indicates that superior cervical ganglionectomy is the useful procedure to increase in cerebral blood flow immediately after the operation on patients with moyamoya disease.     

Response of the cerebral circulation to profound hypocarbia in neonatal lambs

Hyperventilation to extremely low arterial carbon dioxide tension (PaCO2) has been used in the management of persistent pulmonary hypertension in newborn infants. With progressive hypocarbia, cerebral vasoconstriction occurs, raising the concern that extreme hypocarbia may result in cerebral oxygen deprivation. Therefore, I evaluated regulation of the cerebral circulation during acute hypocarbia in 10 newborn lambs. Whole-brain and regional blood flows measured using radioactive microspheres, arterial and venous (sagittal sinus) blood gases, and oxygen contents were measured in each lamb at four arterial carbon dioxide tensions. Whole-brain oxygen delivery, oxygen consumption, and fractional oxygen extraction were calculated. Finally, arterial and venous lactate concentrations were measured to assess cerebral lactate production. Whole-brain blood flow (CBF) decreased in a nonlinear fashion as PaCO2 ranged from 46 to 12 mm Hg [In(CBF) = 0.025(PaCO2) + 3.38; r = 0.70, p less than 0.001]. Similar responses were demonstrated for all regional blood flows examined. Cerebral fractional oxygen extraction (E) increased in a nonlinear fashion [In(1-E) = 0.023(PaCO2)-1.37; r = 0.80, p less than 0.001], and cerebral metabolic rate for oxygen was unchanged with hypocarbia. Cerebral venous lactate concentration increased significantly (3.49 +/- 0.23 vs. 2.01 +/- 0.22 mM, p less than 0.001) during severe hypocarbia (PaCO2 of less than 22 mm Hg), and the arterial-venous lactate concentration difference became negative. These results demonstrate uniform responses of whole-brain and regional blood flows and stable cerebral oxygen consumption during moderate and severe hypocarbia. Although there is evidence for cerebral lactate production during severe hypocarbia, this is not likely to indicate cerebral hypoxia as oxygen consumption does not change.     

Intrinsic and extrinsic mechanisms involved in the cerebrovascular reaction elicited by immobilization stress in rabbits

Variations in cerebral blood flow and partial pressures of oxygen and carbon dioxide (pO₂, pCO₂) were studied in rabbits during short-duration (1 min) immobilization stress. The techniques used enabled us to determine these variables locally in the caudate nucleus in a continuous, simultaneous and quantitative fashion. It could be shown that cerebral blood flow and arterial blood pressure increased in parallel immediately after inducing the stress reaction, and that pO₂ increased further, indicating that cerebral oxygen supply is maintained by the hyperaemia. Previous administration of a β-receptor blocker or of a cholinergic receptor blocker significantly diminished the cerebrovascular reaction to stress, inducing a decrease in pO₂ during the reaction. Administration of both blockers nearly abolished the cerebral vasodilatation studied. Previous administration of an -receptor blocker enhanced the reactive hyperaemia. No disturbance of the blood-brain barrier could be observed in rabbits subjected to stress. Intravenous injection of adrenaline, as well as angiotensin II inducing similar increases in blood pressure, had no comparable effect on the blood flow. The conclusion is that in this model of anxiety, neurogenic mechanisms are involved in the provision of a sufficient oxygen supply to the brain.     

Control for Carbon DioxideRelated Changes in Flow Velocity by Transcranial Doppler Monitoring

Transcranial Doppler ultrasonography can monitor changes in intracranial blood flow velocity over time in a variety of experimental and clinical settings with excellent temporal resolution. Alterations in arterial carbon dioxide pressure exert a profound influence on blood flow velocity. Such changes exhibit important individual fluctuation depending on respiratory status. This limits the ability of transcranial Doppler to accurately study subtle changes in blood flow velocity, independent of the respiratory state of the subject. Suggested here is a method to control for the respiration artifact on blood flow velocity. The middle cerebral artery of 7 healthy male volunteers was studied with transcranial Doppler under resting conditions, monitoring end-tidal carbon dioxide concentration and blood flow velocity. Hyperventilation was performed both voluntarily and with pharmacological induction by human corticotropin-releasing hormone. These studies were carried out both with and without the use of counterregulation of the end-tidal carbon dioxide concentration via a respiration unit, with an adjustable carbon dioxide-oxygen gas supply preventing significant changes in end-tidal carbon dioxide. The blood flow velocity in the middle cerebral artery during maximal voluntary hyperventilation decreased from baseline values of 100% to 44.4 ± 4.3% (a 55.6% decrease), and with human corticotropin- releasing hormone-induced involuntary hyperventilation, to 65.1 ± 5.3% (a 34.9% decrease). With the control method, blood flow velocities during voluntary and pharmacological hyperventilation were 100 ± 1.6% and 100 ± 2.8%, respectively. This method allows for control of respiration-induced artifacts during transcranial Doppler monitoring, and can be used to assess the effect of direct or indirect blood flow velocity stimuli independent of respiratory status.     

Control of cerebral circulation in the high-risk neonate

A knowledge of neonatal cerebrovascular physiology is essential to the understanding of diseases that frequently affect the subsequent development of the newborn brain. Recent observations indicate that the cerebral vessels of the healthy newborn infant, even the very preterm, respond to physiological stimuli in the same manner as in the mature organism. Thus, cerebral blood flow changes with changes in arterial carbon dioxide tension (PaCO2), oxygen concentration (CaO2), or glucose concentration, whereas cerebral blood flow remains constant at minor fluctuations in arterial blood pressure. In pathological states, pressure autoregulation may become impaired, and in severe cases the vessels do not react to chemical or metabolic stimuli. These infants are at high risk for developing cerebral lesion, and they may be candidates for new "brain-protecting regimens."     

Unchanged cerebral blood flow and oxidative metabolism after acclimatization to high altitude.

The authors investigated the effect of acclimatization to high altitude on cerebral blood flow and oxidative metabolism at rest and during exercise. Nine healthy, native sea-level residents were studied 3 weeks after arrival at Chacaltaya, Bolivia (5,260 m) and after reacclimatization to sea level. Global cerebral blood flow at rest and during exercise on a bicycle ergometer was measured by the Kety-Schmidt technique. Cerebral metabolic rates of oxygen, glucose, and lactate were calculated by the Fick principle. Cerebral function was assessed by a computer-based measurement of reaction time. At high altitude at rest, arterial carbon dioxide tension, oxygen saturation, and oxygen tension were significantly reduced, and arterial oxygen content was increased because of an increase in hemoglobin concentration. Global cerebral blood flow was similar in the four conditions. Cerebral oxygen delivery and cerebral metabolic rates of oxygen and glucose also remained unchanged, whereas cerebral metabolic rates of lactate increased slightly but nonsignificantly at high altitude during exercise compared with high altitude at rest. Reaction time was unchanged. The data indicate that cerebral blood flow and oxidative metabolism are unaltered after high-altitude acclimatization from sea level, despite marked changes in breathing and other organ functions.     

Choroid plexus blood flow in the sheep

Choroid plexus blood flow was measured in 29 adult female sheep using the radioactive microsphere technique. Basal blood flow, response to change in arterial carbon dioxide tension, and response to change in mean arterial blood pressure were determined. The results were compared to cerebral cortical blood flow values in the same sheep. Mean choroid plexus blood flow was 601 ml/100 g/min under basal conditions. Choroid plexus blood flow fell 31% with hypocarbia, a reduction comparable to that seen in cortex. With hypercarbia choroid plexus blood flow rose only 27% whereas cortical blood flow increased by 199%. Unlike cortical blood flow, choroid plexus blood flow fell significantly with pharmacogenic hypertension. The latter finding may reflect the absence of a blood-brain barrier in choroid plexus.     

The role of nitric oxide in the regulation of cerebral blood flow

The role of nitric oxide in the cerebral circulation under basal conditions and when exposed to hypoxic, hypercapnic and hypotensive stimuli, was studied in mechanically ventilated rats using a venous outflow technique, by examining the effects of inhibition of nitric oxide synthase with N-nitro-l-arginine methyl ester (l-NAME).l-NAME (10 or 30 mg/kg injected intravenously) raised mean arterial blood pressure by 14% and 24%, and increased cerebrovascular resistance (CVR) by 20% and 24%, respectively. Cerebral blood flow (CBF) was unaltered, as were blood gases and pH. The increases in MABP and CVR were attenuated byl-arginine (300 mg/kg). Following the administration ofl-NAME, the increases in CBF elicited by ventilation with 8% oxygen for 25 s were unaltered, in comparison to control responses.l-NAME attenuated the increases in CBF and reduced the time for recovery to basal flow rates evoked by ventilation with 10% carbon dioxide. These effects were reversed byl-, but not byd-, arginine. Autoregulation by CBF during hypotensive episodes, as measured by comparisons of CVR values, was unaffected byl-NAME. The results suggest that endogenous nitric oxide is involved in the responses of the cerebral vasculature to elevated levels of CO₂ in the arterial blood. Nitric oxide does not appear to play a major role in autoregulation to increases or decreases in MABP, or in hypoxia-evoked vasodilation.     

Preservation of cerebral autoregulation in the unanesthetized hypoxemic newborn dog

Studies were conducted to determine the effects of hypoxemia on cerebral blood flow and the influence of hyperoxia and hypoxemia on autoregulation of cerebral blood flow in the unanesthetized newborn dog. Twenty-one newborn dogs less than 2 weeks of age were studied. Cerebral blood flow was measured using radioactive microspheres during successive periods of normotension, hypotension (produced by blood withdrawal) and normotension (produced by infusion of previously withdrawn blood). In the hyperoxic animals, arterial pO2 was maintained above 250 torr by having the animal breathe 100% oxygen, while in the hypoxemic animals arterial pO2 was maintained between 30 and 35 torr by having the animal breathe 12% O2. Cerebral blood flow increased significantly with hypoxemia. In both hypoxemic and hyperoxic animals cerebral blood flow was maintained constant in spite of a large fall in arterial blood pressure and cardiac output, demonstrating the presence of autoregulation. Calculated oxygen transport to the brain was constant during hypoxemia and hypotension in all animals. Thus autoregulation of cerebral blood flow is present in newborn animals and is preserved under conditions of moderate hypoxemia.     

Changes in Cerebral Blood Flow as Monitored by Transcranial Doppler During Voluntary Hyperventilation and Their Effect on the Electroencephalogram

Hyperventilation results in a fall 1n carbon dioxide concentration, a fall in cerebral blood flow, and slowing of activity on the electroencephalogram. The temporal relationship and duration of these responses are uncertain, and were investigated using Simultaneous monitoring of cerebral blood flow velocity and of the electroencephalograph, with end-tidal carbon dioxide monitoring. Sixteen patients and 9 normal volunteers were studied. Cerebral blood flow velocity in the middle cerebral artery was measured using transer anial Doppler sonography during 3 minutes of hyperventilation and during a 3-minute recovery penod Electroencephalographic recordings were rated by both visual score and measurement of the dominant posterior frequency. End-tidal expired carbon dioxide tension was monitored during the same hyperventilation protocol in the volunteers. Flow velocity fell rapidly during act1ve hyperventilation. Electroencephalographic slowing closely correlated with the decrease in flow velocity (r = 0.86), but lagged behind t. In healthy volunteers capnographic records showed a very tight coupling between end-tidal carbon dioxide concentration and flow velocity (r = 0.94). Three mmutes after hyperventilation, carbon dioxide concentration, cerebral blood flow velocity, and electroencephalographic activity were still not back to the resting state. The fall in both cerebral blood flow velocity and carbon dioxide concentration are related to but precede electroencephalographic slowing. The abnormalities persist for at least 3 minutes after hyperventilation and this must be taken into account in clinical electroencephalography. Transcranial Doppler sonography is well suited to monitoring short-term changes in the cerebral circulation.     

Spontaneous flow oscillations in the cerebral cortex during acute changes in mean arterial pressure.

The purpose of this study was to characterize spontaneous oscillations of blood flow in the cerebral cortex of anesthetized rats under control conditions and after mean arterial pressure was altered by various means. Blood flow was monitored using a laser-Doppler flowmeter through the closed cranium. Spontaneous flow oscillations with amplitudes of 14-30% of the mean flow and frequencies of 4-11 cycles/min were recorded when arterial pressures were less than 90 mm Hg. Stepwise hemorrhagic hypotension and unilateral carotid occlusion increased the amplitude of oscillations. The amplitude of oscillations was negatively correlated with the level of mean arterial pressure after manipulation with norepinephrine or sodium nitroprusside. The oscillations were reversibly abolished during dilation of the cerebral circulation by elevating the inspired carbon dioxide content to 5%. The frequency of flow oscillations was very stable during all of the above maneuvers except during the infusion of norepinephrine, which increased the oscillation frequency slightly. The results suggest that flow oscillations are determined primarily by cerebral arterial pressure.     

Cerebral autoregulation during orthostatic stress in healthy controls and in patients with posturally related syncope

Abstract. Posturally related syncope (PRS) is a common and distressing problem, which frequently occurs in people with no apparent clinical disorder and is ultimately caused by a reduction in blood supply to the brain. The aim of this study was to compare cerebrovascular responses to orthostatic stress in otherwise healthy patients suffering from PRS, and who were shown to have a poor orthostatic tolerance (n=28), with those in healthy control subjects with good orthostatic tolerance (n=11). Responses of heart rate, arterial blood pressure, end tidal carbon dioxide and middle cerebral artery (MCA) blood flow velocity were determined during a progressive orthostatic stress test of combined head-up tilting and lower body suction, which was continued until presyncope. We assessed the efficiency of autoregulation of cerebral blood flow from the relationship between values of MCA velocity and pressure obtained over the expected range for autoregulation (> 55mmHg). All patients with PRS had a significant correlation between MCA velocity and pressure, but this was seen in only two of the controls. Furthermore, the values of the correlation coefficients were significantly higher in patients than controls, (p<0.001). We interpret these data as indicating that autoregulation in patients with PRS is less effective than in controls and suggest that this provides evidence for a link between abnormalities of regulation of the cerebral circulation and predisposition to syncope.     

Cerebral hemodynamics and metabolism in pseudotumor cerebri

A comprehensive analysis of cerebral hemodynamics and metabolism was carried out in 14 patients with pseudotumor cerebri. Tracer techniques were employed to measure cerebral blood flow (CBF) and vascular reactivity to acute changes in arterial carbon dioxide tension and blood pressure, cerebral blood volume (CBV), and the cerebral metabolic rate for oxygen and glucose. There was a small reduction (p < 0.01) in CBF (44 ± 7 ml/100 gm/min; normal, 54 ± 9) with normal vascular reactivity; an increase (p < 0.005) in CBV (4.8 ± 0.8 ml/100 gm; normal, 3.6 ± 0.5), and normal cerebral metabolism. We conclude that an abnormality of the cerebral microvasculature is responsible for an elevation in CBV, but the intracranial hypertension can be explained only by tissue swelling due to an increase in water content. The relationship between the vascular abnormality and the tissue swelling remains to be defined.     

Effect of adrenergic drugs on cerebral blood flow, metabolism, and evoked potentials after delayed cardiopulmonary resuscitation in dogs

BACKGROUND AND PURPOSE: Epinephrine administration during cardiopulmonary resuscitation increases cerebral blood flow by increasing arterial pressure. We tested whether potential beta-adrenergic effects of epinephrine directly influence cerebral blood flow and oxygen consumption independently of raising perfusion pressure. METHODS: Four groups of seven anesthetized dogs were subjected to 8 minutes of fibrillatory arrest followed by 6 minutes of chest compression, ventricular defibrillation, and 4 hours of spontaneous circulation. Cerebral perfusion pressure was increased to approximately equivalent ranges during resuscitation by either 1) epinephrine infusion, 2) epinephrine infusion after pretreatment with the lipophilic beta-adrenergic antagonist pindolol, 3) infusion of the alpha-adrenergic agonist phenylephrine, or 4) descending aortic balloon inflation without pressor agents. RESULTS: We found no difference in cerebral blood flow, oxygen extraction, or oxygen consumption during chest compression among groups. After ventricular defibrillation, depressed levels of cerebral blood flow, cerebral oxygen consumption, and somatosensory evoked potential amplitude were not different among groups. CONCLUSIONS: We detected no evidence that after 8 minutes of complete ischemia, epinephrine administration during resuscitation substantially influences cerebral blood flow or cerebral oxygen consumption independent of its action of raising arterial pressure or or that epinephrine has a negative impact on immediate metabolic or electrophysiological recovery attributable to its beta-adrenergic activity.     

Regulation of regional cerebral blood flow during and between migraine attacks

Cerebrovascular reactivity to voluntary hyperventilation, moderate hypertension, and physiological activation was studied in nine patients during induced migraine attacks and in four patients between their attacks. Regional cerebral blood flow was measured by the xenon 133 injection technique in 254 areas of one hemisphere. The partly hypoperfused hemisphere allowed for comparison of adjacent hypoperfused and normally perfused brain areas. During attacks the carbon dioxide reactivity was decreased to 2.8 +/- 0.8% per mm Hg in the oligemic regions compared with 5.8 +/- 0.8% per mm Hg in the normally perfused brain. Blood pressure autoregulation was normal in all brain regions. Regional blood flow increase in response to physiological activation was severely impaired in the hypoperfused brain areas, whereas neighboring normally perfused regions reacted normally. Confinement of the regulation abnormalities to the area of the oligemia supports our suggestion that the blood flow changes are caused by a change in local metabolism. Between attacks of migraine, the patients had normal regulation of brain circulation.