Effects of endothelium-derived nitric oxide on cerebral circulation during normoxia and hypoxia in the rat.

The aim of this study was to determine the effects of endogenous nitric oxide (NO) on cerebral blood flow (CBF) and cerebrovascular resistance (CVR) under conditions of normoxia and hypoxia. Experiments were performed on anesthetized, mechanically ventilated Wistar rats. CBF was measured using the intracarotid 133Xe injection technique. NO formation was inhibited by NG-monomethyl-L-arginine (L-NMMA). Administration of L-NMMA (100 mg kg-1 i.v.) during normoxia resulted in an increase in mean arterial blood pressure from 113 +/- 4 to 145 +/- 4 mm Hg (p less than 0.001), a decrease in CBF of 21% (from 91 +/- 4 to 75 +/- 5 ml 100 g-1 min-1, p less than 0.001), and an increase in CVR of 53% (from 1.3 +/- 0.1 to 2.0 +/- 0.2 mm Hg ml-1 100 g min, p less than 0.001). These effects were reversed by i.v. administration of 300 mg kg-1 of L-arginine but not D-arginine. Moreover, the administration of L-NMMA abolished the enhancement of CBF and the diminution in CVR observed during intracarotid infusion of acetylcholine (ACh). The increase in CBF and decrease in CVR during hypoxia in the group of rats that received L-NMMA were similar to that in the control group, although CBF and CVR levels attained during hypoxia in both groups were different. The results show that NO is involved in the maintenance of basal CBF and CVR, and is responsible for the ACh-elicited increase in CBF and the decrease in CVR in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of combined hypoxemia and cephalic hypotension on fetal cerebral blood flow and metabolism

The effect of hypoxemia and cephalic hypotension, alone and in combination, on hemispherical CBF and metabolism was examined in seven chronically catheterized fetal sheep. Hypoxemia was induced by lowering the maternal inspired oxygen fraction and cephalic hypotension was generated by partial occlusion of the fetal brachiocephalic artery. CBF was measured with radionuclide-labeled microspheres. During control, the arterial blood oxygen content (CaO2) was 3.2 +/- 1.0 (SD) mM and CBF averaged 131 +/- 21 (SD) ml min-1 100 g-1. The cephalic perfusion pressure (PP, mean cephalic arterial-sagittal venous) was 40 +/- 4 mm Hg and cerebral vascular resistance (CVR, PP/CBF) was 0.31 +/- 0.06 mm Hg ml-1 min 100 g. During induced hypoxemia, CaO2 was 1.4 +/- 0.7 mM and CBF was elevated to 223 +/- 60 ml min-1 100 g-1. PP was not different from control and CVR was lower at 0.19 +/- 0.04 mm Hg ml-1 min 100 g, reflecting cerebral vasodilation. With cephalic hypotension alone (PP = 21 +/- 4 mm Hg; CaO2 = 3.4 +/- 0.9 mM), CBF fell to 83 +/- 23 ml min-1 100 g-1 and there was no significant change in CVR (0.26 +/- 0.05 mm Hg ml-1 min 100 g). During combined hypoxemia and hypotension (CaO2 = 1.5 +/- 0.8 mM and PP = 18 +/- 4 mm Hg), CBF was significantly greater than during hypotension alone (100 +/- 6 ml min-1 100 g). CVR was 0.19 +/- 0.05 mm Hg ml-1 min 100 g, identical to that measured in normotensive hypoxemia and significantly less than found during hypotension alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influences of caffeine, acetazolamide and cognitive stimulation on cerebral blood flow velocities

Assessment of cerebral blood flow velocities (CBFV) can be used as a non-invasive tool to evaluate specific drug effects, like caffeine (CAF), acetazolamide (AA) as well as cognition. Their influences on each others CBFV were evaluated in detail, using a randomized, double-blind, double-dummy, placebo-controlled three-fold cross-over study design in 18 right-handed healthy male volunteers. CBFV (maximal, mean, minimal) and pulsatility index of both middle cerebral arteries were recorded by transcranial Doppler ultrasound simultaneously, during a verbal memory test, oral CAF, intravenous AA or placebo. AA led to increase in CBFV of 25-32%. Caffeine resulted in decreased V(mean) and V(min) of 10-13%. Cognitive stimulation resulted in a slight increase of CBVF of about 4%, but was overruled by effects of AA and CAF. We conclude that pharmacological effects can easily be assessed by TCD during clinical pharmacological studies of vasoactive drugs. However intraindividual variability and effects of neuropsychological stimulation needs to be taken into account.     

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.     

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.     

Acute exposure to normobaric mild hypoxia alters dynamic relationships between blood pressure and cerebral blood flow at very low frequency.

Acute hypoxia directly causes cerebral arteriole vasodilation and also stimulates peripheral chemoreceptors to change autonomic neural activity. These changes may alter cerebral vascular modulation. We therefore hypothesized that dynamic cerebral autoregulation would be altered during acute exposure to hypoxia. Fifteen healthy men were examined under normoxic (21%) and hypoxic conditions. Oxygen concentrations were decreased in stepwise fashion to 19%, 17%, and 15%, for 10 mins at each level. Mean blood pressure (MBP) in the radial artery was measured via tonometry, and cerebral blood flow velocity (CBFV) in the middle cerebral artery was measured by transcranial Doppler ultrasonography. Dynamic cerebral autoregulation was assessed by spectral and transfer function analysis of beat-by-beat changes in MBP and CBFV. Arterial oxygen saturation decreased significantly during hypoxia, while end-tidal CO2 and respiratory rate were unchanged, as was steady-state CBFV. With 15% O2, very-low-frequency power of MBP and CBFV variability increased significantly by 185% and 282%, respectively. Moreover, transfer function coherence (21% O2, 0.46+/-0.04; 15% O2, 0.64+/-0.04; P=0.028) and gain (21% O2, 0.61+/-0.05 cm/secs/mm Hg; 15% O2, 0.86+/-0.08 cm/secs/mm Hg; P=0.035) in the very-low-frequency range increased significantly by 53% and 48% with 15% O2, respectively. However, these indices were unchanged in low- and high-frequency ranges. Acute hypoxia thus increases arterial pressure oscillations and dependence of cerebral blood flow (CBF) fluctuations on blood pressure oscillations, resulting in apparent increases in CBF fluctuations in the very-low-frequency range. Hypoxia may thus impair dynamic cerebral autoregulation in this range. However, these changes were significant only with hypoxia at 15% O2, suggesting a possible threshold for such changes.     

TMB—8对脑缺血大鼠脑血流量的作用

目的 研究8－（N，N－二乙胺）－n－辛基－3，4，5－三甲氧基苯甲酸酯（TMB－8）对局灶性脑缺血大鼠脑血流量（CBF）的作用。方法 用激光多谱勒血流仪测量大脑中动脉阻断（MCAO）大鼠脑血流量。分别于阻断前30分钟和阻断后20分钟给予TMB－8进行干预。结果 MCAO后，CBF迅速下降，维持恒定。阻断前30分钟给予TMB－8 0．5、1和2mg/kg，可剂量依赖性抑制CBF下降，阻断后20分钟给予TMB－8 1mg/kg，也能明显增加CBF。结论 TMB－8能预防和治疗MCAO局灶性脑缺血大鼠CBF减少，改善缺血区血供。     

MK-801 attenuates capillary bed compression and hypoperfusion following incomplete focal cerebral ischemia

The effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on capillary beds and CBF following 1 h of transient incomplete focal cerebral ischemia were studied by examining 133Xe CBF, capillary diameter, and area of perfused vasculature. Capillary diameter increased from a control of 5.24 +/- 0.37 to 8.62 +/- 0.57 microns (p less than 0.001) and area of perfused vasculature from 20,943 +/- 1,151 to 30,442 +/- 1,691 microns2/x 10 magnification field (p less than 0.001) with MK-801 1.0 mg/kg administered 30 min prior to ischemia. After flow restoration in control animals, there was a relative hypoperfusion with eventual normalization of CBF over 60 min. Alternatively, in MK-801 1.0 mg/kg animals, there was rapid normalization of CBF upon flow restoration without the postischemic hypoperfusion observed in controls. On histological analysis, there was consistently less neuronal edema in MK-801-treated animals. These results support the hypothesis that hypoperfusion following incomplete focal cerebral ischemia may be due in part to NMDA-mediated cellular edema with subsequent extravascular capillary bed compression.     

Evaluation of cerebral hemodynamics with perfusion CT]

We report on the evaluation of cerebral ischemic lesions with perfusion CT. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) of 52 patients mostly with ischemic cerebrovascular disease were analysed using the box-modulation transfer function method with 30 ml of contrast medium intravenously injected at 5 ml/sec. CBF, CBV and MTT of the middle cerebral artery (MCA) territory were 43.5 +/- 4.6 ml/100 g/min, 1.9 +/- 0.2 ml/100 g and 2.9 +/- 0.6 seconds at the unaffected side, and 37.7 +/- 7.3 ml/100 g/min, 2.1 +/- 0.3 ml/100 g, 3.7 +/- 0.9 seconds at the lesion side with stenosis or occlusion in the main MCA trunks or internal carotid artery, respectively. A statistically significant difference was shown in CBF and MTT values. Furthermore, there was a close correlation in CBF values of MCA territories between Xe-CT and perfusion CT (r = 0.645, n = 76, p < 0.0001). MTT showed a positive correlation with CBV in those subjects when MTT was below 4.1 seconds (r = 0.526, p < 0.0001, n = 83). MTT also showed a negative correlation with CBF in those patients when MTT indicated more than 4.1 seconds (r = 0.818, p < 0.001, n = 21). These results suggest that the progression of cerebral ischemia may be classified in 4 stages using perfusion CT. The stages are as follows: stage 0; normal CBF without prolonged MTT and increased CBV, stage 1; relatively increased CBV, stage 2; significantly prolonged MTT, and stage 3; significantly decreased CBF with prolonged MTT.     

Cerebral blood flow during dihydralazine-induced hypotension in hypertensive rats

The cerebrovascular effects of graded, controlled dihydralazine-induced hypotension were studied in rats with renal hypertension (RHR) and spontaneous hypertension (SHR). Repeated measurements of cerebral blood flow (CBF) were made using the intraarterial 133Xenon injection technique in anaesthetised normocapnic animals. Dihydralazine was administered in single increasing i.v. doses (0.1 to 2 mg/kg), and CBF measured after each dose when a stable blood pressure had been reached. From a resting level of 145 +/- 7 mm Hg in RHR and 138 +/- 11 mm Hg in SHR, mean arterial pressure (MAP) fell stepwise to a minimum of around 50 mm Hg. CBF was preserved during dihydralazine induced hypotension, and remained at the resting level of 79 +/- 13 ml/100 g . min in RHR and 88 +/- 16 ml/100 g . min in SHR. Following 2 hours hypotension at the lowest pressure reached, the rats were sacrificed by perfusion fixation and the brains processed for light microscopy. Evidence of regional ischaemic brain damage was found in 4 of 11 animals: in 2 cases the damage appeared to be accentuated in the arterial boundary zones. Although the lower limit of CBF autoregulation in these rats is around 100 mm Hg during haemorrhagic hypotension, dihydralazine brought MAP to around 50 mm Hg without any concomitant fall in CBF. This was interpreted as being due to direct dilatation of cerebral resistance vessels. The combination of low pressure and direct dilatation may have resulted in uneven perfusion, thus accounting for the regional ischaemic lesions.     

Opioids and the prostanoid system in the control of cerebral blood flow in hypotensive piglets

The interaction between opioid and prostanoid mechanisms in the control of cerebral hemodynamics was investigated in the conscious hypotensive piglet. Radiomicrospheres were used to determine regional cerebral blood flow (rCBF) in piglets pretreated with the opioid receptor antagonist, naloxone, or its vehicle, saline, during normotension, hypotension, and after the administration of indomethacin, a cyclooxygenase inhibitor, during hypotension. Hemorrhage (30 ml/kg) decreased systemic arterial pressure from 68 +/- 12 to 40 +/- 10 mm Hg but did not decrease blood flow to any brain region. Indomethacin treatment (5 mg/kg) of hypotensive piglets decreased blood flow to all brain regions within 20 min; this decrease in CBF resulted from increases in cerebral vascular resistance of 65 and 281% at 20 and 40 min after treatment, respectively. In hypotensive piglets, cerebral oxygen consumption was reduced from 2.62 +/- 0.71 to 0.53 +/- 0.27 ml 100 g-1 min-1 and to 0.11 +/- 0.04 ml 100 g-1 min-1 at 20 and 40 min following indomethacin, respectively. Treatment with naloxone (1 mg/kg) had no effect on rCBF, calculated cerebral vascular resistance, or cerebral oxygen consumption of normotensive or hypotensive piglets. However, decreases in CBF and oxygen consumption and increases in cerebral vascular resistance upon treatment of hypotensive piglets with indomethacin were attenuated in animals pretreated with naloxone. These data indicate that the removal of prostanoid modulation of an opioid-mediated constrictor influence on the cerebral circulation is a potential mechanism for the increase in cerebral vascular resistance that follows indomethacin treatment of hypotensive piglets.     

Endothelium-derived nitric oxide synthase inhibition. Effects on cerebral blood flow, pial artery diameter, and vascular morphology in rats.

BACKGROUND AND PURPOSE: We determined the effects of inhibiting the production of cerebral endothelium-derived nitric oxide on pial artery diameter, cortical blood flow, and vascular morphology. METHODS: An inhibitor of endothelium-derived nitric oxide synthesis, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), or an equivalent volume of 0.9% saline was infused into rats intra-arterially in a retrograde fashion via the right external carotid artery at a rate of 3 mg/kg/min to a total dose of 190 mg/kg or intravenously at 1 mg/kg/min to a total dose of 15 mg/kg. Large pial arteries were continuously visualized through an operating microscope, and cortical cerebral blood flow was monitored by laser-Doppler flowmetry. To localize areas of morphological interest, the protein tracer horseradish peroxidase was injected 15 minutes before termination of the L-NAME infusion and the rats were perfusion-fixed 15 minutes later for light and electron microscopic analysis. RESULTS: Infusion of L-NAME significantly raised arterial blood pressure at both doses (for 190 mg/kg, from 103.2 +/- 3.4 to 135 +/- 3.4 mm Hg; for 15 mg/kg, from 125 +/- 2.8 to 144.4 +/- 4.0 mm Hg). Pial arteries constricted within 10 minutes after the start of the intracarotid infusion to 40% of the preinfusion diameter, while cortical cerebral blood flow decreased to an average of 72.5% of that at baseline. Morphological abnormalities in the experimental rats included microvascular stasis and focal areas of blood-brain barrier disruption to protein. Ultrastructural examination of cortical leaky sites revealed constricted arterioles with many endothelial pinocytotic vesicles and microvilli. CONCLUSIONS: These observations suggest that inhibition of endothelium-derived nitric oxide synthesis affects the relation between cerebral arterial diameter and cerebral blood flow and can lead to subtle cerebral vascular pathological changes consistent with focal brain ischemia.     

Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone and in combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) on outcome from transient focal cerebral ischemia in the rat. Halothane anesthetized rats (n=20 per group) were given saline or a single 15-min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats (n=12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 alone did not significantly reduce infarct size or improve neurologic score. A dose-response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO. Dizocilpine (0.5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%. Other rats were then subjected to 75 min of MCAO after being given dizocilpine (0.25 mg/kg i.v.; n=18) or RSR13 (150 mg/kg i.v. )+dizocilpine (0.25 mg/kg i.v.; n=15). RSR13+dizocilpine resulted in smaller cortical infarct volume (8+/-14 mm3 vs. 34+/-37 mm3, p<0.02) and total cerebral infarct volume (46+/-28 mm3 vs. 81+/-60 mm3, p<0. 05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P50 of approximately 25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.     

Tissue plasminogen activator cerebrovascular thrombolysis in rabbits is dependent on the rate and route of administration.

BACKGROUND AND PURPOSE: The main aim of our study was to assess the cerebrovascular thrombolytic efficacy of different tissue plasminogen activator treatment protocols with Doppler ultrasound. METHODS: We occluded one internal carotid artery in 48 New Zealand White rabbits with whole blood emboli. Five minutes later the rabbits were assigned to receive one of the following tissue plasminogen activator protocols: 1) intravenous square-wave infusion in a total dose of 10 mg/kg, 2) intravenous constant infusion in a total dose of 10 mg/kg, 3) intravenous square-wave infusion in a total dose of 3 mg/kg, or 4) regional intra-arterial square-wave infusion in a total dose of 3 mg/kg. Blood flow velocities in the internal carotid arteries were continuously monitored during the study with Doppler ultrasound. RESULTS: In all 12 animals treated with a 10-mg/kg square-wave intravenous tissue plasminogen infusion, internal carotid artery blood flow was reestablished within 2 hours (57.9 +/- 33.3 minutes) after the initiation of treatment, whereas this was the case for only six (50%) of the 12 animals treated with a constant 10-mg/kg intravenous tissue plasminogen activator infusion (p less than 0.05, Fisher's exact test). Internal carotid artery blood flow was restored within 2 hours (33.5 +/- 40.4 minutes) in all animals treated with a regional intra-arterial tissue plasminogen infusion in a total dose of 3 mg/kg and in only three (50%) of the six animals treated with the same dosage intravenously (p less than 0.05, signed rank test). CONCLUSIONS: The thrombolytic efficacy of tissue plasminogen activator in the rabbit cerebral vasculature was superior when the same intravenous dose was given as a square-wave rather than a constant infusion and when the drug was given as a regional intra-arterial infusion rather than intravenously.     

Asymmetry of the cerebral blood flow: An ultrasound Doppler study in preterm newborns

The purpose of this study was to investigate whether the preference of periventricular hemorrhage (PVH) for the left hemisphere is due to asymmetry of cerebral blood flow (CBF) and, if so, whether this asymmetry is due to patent ductus arteriosus (PDA). Thirty-three preterm newborns at risk for PVH were followed during their first 5 days after birth. Internal carotid CBF velocity (CBFV) and the flow direction in the common pulmonary artery, both determined by ultrasound Doppler, served as measures of CBF and PDA, respectively. The difference between right and left CBFV was analyzed statistically, with outcome, PDA, capillary P ₂, behavior, heart rate, and the average of right and left CBFV as covariates. Infants who developed PVH (n = 7) exhibited CBFV asymmetry to the disadvantage of the left side. This finding was partially attributable to PDA. Without PVH there was no significant CBFV asymmetry. Because all hemorrhages were bilateral, a relationship with the side of the hemorrhage could not be explored. In conclusion, asymmetry of CBFV is not normal, but is associated with PVH and PDA.     

Assessment of cerebrovascular reserve in unilateral middle cerebral artery stenosis using perfusion CT and CO2 inhalation tests

Purpose/Aim of the study: Cerebrovascular reactivity (CVR) is an important marker for assessing cerebrovascular disease. This study assessed the CVR by perfusion computed tomography (CT) and CO₂ inhalation tests in patients with unilateral middle cerebral artery (MCA) stenosis disease. Materials and Methods: Thirty-one patients with unilateral MCA stenosis disease diagnosed by digital subtraction angiography were studied. Patients were divided into two groups according to the degree of stenosis: severe and moderate. The regional cerebral blood flow (CBF) before and after CO₂ inhalation was determined by perfusion CT. Regional CVR values were obtained by the following formula: increase (%) = (post-CBF) ? (pre-CBF)/(pre-CBF) × 100%. Results: No significant differences in the mean CBF in the MCA stenosis region were found between the affected and contralateral sides before the CO₂ inhalation test; after the test, CBF was more significantly decreased on the affected side than on the contralateral side. The changes in CBF on the affected side were categorized into three types: increased CBF (17 cases), decreased CBF (12 cases) and no change in CBF (2 cases). The rate of CVR impairment among severe stenosis patients (13/19) was higher than that among moderate stenosis patients (3/12). CVR was significantly correlated with the degree of stenosis (r = 0.423, P = 0.018). Conclusion: CVR impairment was found in approximately half of patients with unilateral MCA stenosis. Along with an increase in the degree of stenosis, patients with unilateral MCA stenosis were more likely to exhibit CVR impairment. It is important to assess the CVR in patients with unilateral MCA stenosis, especially those with severe stenosis.     

The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats.

The goal of the present study was to test the impact of administration time of the angiotensin II type 1-receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 +/- 8), infarct size in candesartan-treated groups was smaller (59 +/- 5, 68 +/- 10, 28 +/- 3, and 15 +/- 3, respectively; P<0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 +/- 0.18, 1.80 +/- 0.13), other treatment regimens resulted in improved neuroscores (1.33 +/- 0.16, 1.11 +/- 0.11, 0.73 +/- 0.15; P<0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 +/- 0.09 mL x g(-1) x min(-1) and 44% +/- 7% of baseline compared with 0.49 +/- 0.06 mL x g(-1) x min(-1) and 37% +/- 6%, microspheres and laser-Doppler flowmetry; P<0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.     

Is the acetazolamide test valid for quantitative assessment of maximal cerebral autoregulatory vasodilation? An experimental study

BACKGROUND AND PURPOSE: The cerebral vasodilating effect of acetazolamide (ACZ) injection has been used as an index of the autoregulatory vasodilation (or cerebral perfusion reserve). The question of whether the ACZ test assesses the maximal autoregulatory vasodilating capacity is not definitely resolved. The effects of ACZ injection on this reserve at a dose producing maximal vasodilation have never been evaluated and may help to resolve this problem. METHODS: The effect of ACZ injection on cerebral blood flow (CBF) autoregulation was tested in anesthetized rats. A pilot experiment evaluated the dose-effect relationship of injected ACZ, cumulative doses (n=4, group 1), and independent bolus doses (n=6, group 2). CBF was estimated by laser-Doppler flowmetry, and cerebrovascular resistance (CVR) was calculated from mean arterial blood pressure (MABP) and from CBF (expressed as a percentage of baseline CBF). A bolus of ACZ of 21 mg/kg produced the maximal cerebral vasodilation that could be obtained by ACZ administration. In the main experiment, MABP was lowered from 110 to 20 mm Hg by stepwise bleeding in 3 groups of 6 animals treated 10 minutes before bleeding by injection of saline (group 3), 7 mg/kg ACZ (group 4), or 21 mg/kg ACZ (group 5). RESULTS: The CVR-MABP relationship was linear in all groups, indicating that CBF autoregulation was still effective after ACZ administration. CONCLUSIONS: These results indicate that maximal ACZ-induced cerebral vasodilation is not quantitatively equivalent to maximal autoregulatory vasodilating capacity in anesthetized rats.     

Role of prostaglandins in modulating sympathetic vasoconstriction in the cerebral circulation in anesthetized rabbits

The effects of the interaction between sympathetic nerves and prostaglandins in the cerebral circulation were examined. The hypothesis tested was that inhibition of prostaglandin synthesis by indomethacin would potentiate decreases in CBF caused by sympathetic nerve stimulation. In anesthetized rabbits, following administration of either indomethacin (10 mg/kg) or vehicle, CBF was measured with 15-micron microspheres prior to stimulation and following 3-5 min of electrical stimulation (4, 8, 16 Hz) of both superior cervical ganglia. In the vehicle group, CBF was 33-42 ml/min/100 g prior to stimulation. Bilateral sympathetic stimulation reduced blood flow to the cerebrum by 12 +/- 6% (mean +/- SEM) (p less than 0.05) at 4 Hz (n = 8), by 20 +/- 4% (p less than 0.05) at 8 Hz (n = 12), and 21 +/- 6% (p less than 0.05) at 16 Hz (n = 11). In the indomethacin group, CBF was 37-48 ml/min/100 g prior to stimulation. Bilateral stimulation decreased blood flow to the cerebrum by 7 +/- 5% (NS) at 4 Hz (n = 8), by 25 +/- 3% (p less than 0.05) at 8 Hz (n = 6), and by 20 +/- 6% (NS) at 16 Hz (n = 6). Decreases in CBF during nerve stimulation were blocked by prazosin, an alpha-adrenergic antagonist. In additional experiments, cerebral vascular constrictor responses to hypocapnia were found to be similar in the vehicle and indomethacin groups. This study provides evidence that sympathetic nerves can decrease CBF substantially even at low stimulation frequencies. Further, results of this study indicate that prostaglandins do not attenuate the effects of sympathetic stimulation on the cerebral circulation.     

Effect of doxapram on cerebral blood flow velocity in preterm infants

BACKGROUND: Doxapram is used to treat apnea of prematurity when there is an insufficient response to methylxanthine treatment. As an unwanted side effect, reduced cerebral perfusion has been seen in methylxanthine-treated infants while effects of doxapram on the cerebral perfusion have not been studied yet. PATIENTS AND METHODS: Fifteen preterm infants treated with doxapram were included in the study. Birth weight ranged from 380 g to 1150 g (median 740 g), gestational age from 24 to 27 weeks (median 26 weeks). Infants received a doxapram loading dose (2.5 mg/kg) over a 30-minute period, followed by a continuous infusion of 0.5 mg/kg/h. Using Doppler sonography, blood flow velocities and the resistance index were measured in the anterior cerebral artery. Measurements were performed at baseline and 30 and 120 minutes after the start of doxapram. RESULTS: Maximal systolic blood flow velocity (V(max)) decreased significantly after the infants had received the loading dose (V(max) baseline: 40.7 cm/s +/- 6.9 [mean +/- SD]; V(max) 30 min: 35 cm/s +/- 8.9; p = 0.0017) but returned to near baseline values at 120 min (38.5 +/- 9.0, p = 0.22). End-diastolic, time-averaged, and time-averaged maximal velocities did not change significantly at 30 or 120 min. CONCLUSIONS: Doxapram induced a significant decrease in maximal cerebral blood flow velocity. Further studies are needed to assess whether this decrease may be critical to cerebral white matter perfusion in the vulnerable preterm infant.