BJA Advance Access originally published online on September 6, 2006
British Journal of Anaesthesia 2006 97(5):617-623; doi:10.1093/bja/ael238
ß2 Adrenergic antagonist inhibits cerebral cortical oxygen delivery after severe haemodilution in rats
1 Department of Anaesthesia and the Cara Phelan Centre for Trauma Research, University of Toronto, St Michael's Hospital 30 Bond Street, Toronto, Ontario M5B 1W8, Canada
2 Department of Physiology, University of Toronto 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada
*Corresponding author: Department of Anaesthesia and Physiology, University of Toronto, St Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. E-mail: hareg{at}smh.toronto.on.ca
Accepted for publication June 19, 2006.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Background. Haemodilution has been associated with neurological morbidity in surgical patients. This study tests the hypothesis that inhibition of cerebral vasodilatation by systemic ß2 adrenergic blockade would impair cerebral oxygen delivery leading to tissue hypoxia in severely haemodiluted rats.
Methods. Under general anaesthesia, cerebral tissue probes were placed to measure temperature, regional cerebral blood flow (rCBF) and tissue oxygen tension (PBrO2) in the parietal cerebral cortex or hippocampus. Baseline measurements were established before and after systemic administration of either a ß2 antagonist (10 mg kg–1 i.v., ICI 118, 551) or saline vehicle. Acute haemodilution was then performed by simultaneously exchanging 50% of the estimated blood volume (30 ml kg–1) with pentastarch. Arterial blood gases (ABGs), haemoglobin concentration (co-oximetry), mean arterial blood pressure (MAP) and heart rate (HR) were also measured. Data were analysed using a two-way ANOVA and post hoc Tukey's test [mean (SD)].
Results. Haemodilution reduced the haemoglobin concentration comparably in all groups [71 (9) g litre–1]. There were no differences in ABGs, co-oximetry, HR and MAP measurements between control and ß2 blocked rats, either before or 60 min after drug or vehicle administration. In rats treated with the ß2 antagonist there was a significant reduction in parietal cerebral cortical temperature, regional blood flow and tissue oxygen tension, relative to control rats, 60 min after haemodilution (P<0.05 for each). These differences were not observed when probes were placed in the hippocampus.
Conclusion. Systemic ß2 adrenergic blockade inhibited the compensatory increase in parietal cerebral cortical oxygen delivery after haemodilution thereby reducing cerebral cortical tissue oxygen tension.
Keywords: ß2 adrenergic blockade; cerebral blood flow; cerebral tissue oxygen tension; cerebral hypoxia; haemodilution
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Acute haemodilution has been associated with cognitive and neurophysiological dysfunction in healthy volunteers1 2 and increased neurological injury and mortality in perioperative patients by currently undefined mechanisms.3–6 Experimental evidence suggests that haemodilution may augment cerebral injury by limiting cerebral tissue oxygen delivery.7 However, evidence of cerebral tissue hypoxia after severe haemodilution has been difficult to demonstrate,8 9 possibly because of the compensatory increase in cerebral blood flow (CBF). The well-characterized increase in CBF after haemodilution is proportional to the reduction in haematocrit and occurs by passive changes in blood rheology and active cerebral vasodilatation.10–12 However, the mechanism by which active cerebral vasodilatation occurs, or its physiological significance, have not been fully defined.
The cerebral vasculature is richly supplied by a variety of different perivascular neurons which release vasodilating neurotransmitters including nitric oxide (NO).13 Several studies have suggested that perivascular NO-producing neurons play a significant role in regulating CBF in response to a variety of physiological and pharmacological stimuli.10 14–16 Experimental evidence suggests that NO released from perivascular cerebral neurons is regulated by stimulation of pre-synaptic ß2 adrenergic receptors.14 17 Stimulation of these ß2 adrenergic receptors releases NO in the region of cerebral blood vessels resulting in cerebral vasodilatation and a regulated increase in CBF.14 17 The current study tests the hypothesis that ß2 adrenergic mediated cerebral vasodilatation maintains CBF and oxygen delivery after acute haemodilution in rats. Results suggest that systemic ß2 adrenergic blockade attenuated the increase in cerebral cortical oxygen delivery which occurs after severe haemodilution, resulting in a reduction in cerebral tissue oxygen tension.18
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Animal model
All animal protocols were approved by the Animal Care and Use Committee at St Michael's Hospital in accordance with the requirements of the Canadian Council on Animal Care. Anaesthesia was induced in male Sprague–Dawley rats (Charles River, St Constant, PQ, Canada) with isoflurane 3–4% in 100% oxygen in an induction chamber and maintained with isoflurane 1–2% (Abbott, St Laurent, PQ, Canada) in 50% oxygen administered via nose cone. After tracheotomy, ventilation was maintained with a pressure-controlled ventilator (Kent Scientific, Litchfield, CT, USA). Cannulation of the right tail vein and tail artery (Angiocath 24G, BD Medical, Oakville ON, Canada) was performed to achieve vascular access for direct measurement of mean arterial blood pressure (MAP) and arterial blood gases (ABGs) and to perform acute haemodilution. ABGs and co-oximetry were performed at baseline (10 min) and after haemodilution (60 min) (Radiometer ALB 500 and OSM 3; London Scientific, London, ON, Canada).
Anaesthetized animals were placed in a stereotaxic frame (ADI Instruments; Harvard Apparatus, Saint Laurent, PQ, Canada), and the scalp was incised sagittally. Bilateral 5 mm diameter burr holes were trephined at the level of the dura, 1–2 mm lateral to the midline and 3–4 mm posterior to the bregma. A combined oxygen sensitive microelectrode, laser Doppler flow probe and temperature probe (OxyLite and OxyFlo; Oxford Optronix, Oxford, UK) was inserted through the dura, 1–2 mm deep into the cerebral cortex or 3–4 mm deep into the hippocampus using stereotaxic coordinates. A heating pad and heating lamp were used to maintain the brain temperature close to 34°C in order to simulate the body temperature of a patient who had suffered from acute blood loss and fluid resuscitation in the operating room.
Experimental protocol
Two groups of animals were studied to determine the physiological effects of ß2 adrenergic antagonism on either hippocampal or parietal cerebral cortical oxygen delivery. Within each group, animals were divided into two arms: the control arm received saline while the experimental arm received the ß2 antagonist. In the hippocampal group, the cerebral probe was placed 3–4 mm past the dura into the region of the hippocampus in both control (n=7) and ß2 antagonist arms (n=6). In the cerebral cortical group, the probe was placed 1–2 mm past the dura into the region of the parietal cerebral cortex in both control (n=9) and ß2 antagonist arms (n=10). These two groups are subsequently referred to as the hippocampal and cerebral cortical groups. Each group contains a saline control and ß2 antagonist arm. Rats were randomly assigned to each of the four arms until n=6 successful cerebral tissue oxygen tension measurements were obtained for each arm. Cerebral tissue oxygen tension measurements were excluded if baseline tissue oxygen tension values were below 5 torr. Cerebral tissue oxygen tension measurements were more difficult to obtain in the cerebral cortical group. Therefore, a larger number of rats were required in each arm of this group.
In all arms, an initial 20 min baseline was established (Baseline #1). At 20 min, either the ß2 adrenergic antagonist (10 mg kg–1 i.v. in 1 ml saline, ICI 118,551, ((±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol) hydrochloride) (Biomol Int. obtained from Cedarlane Laboratories Ltd, Hornby, ON) or saline (1 ml) was administered slowly over 10 min. Previous experimental studies demonstrate that the ß2 antagonist ICI 118,551 is capable of crossing the blood–brain barrier.14 19 20 After ß2 antagonist or saline administration, a second 20 min baseline was established (Baseline #2). All groups were then haemodiluted by simultaneously exchanging 30 ml kg–1 of arterial blood (50% of estimated total blood volume). Blood was withdrawn from the tail artery and replaced with an equivalent volume of warm pentastarch (37°C) via the tail vein (Pentaspan; Bristol-Myers Squibb Canada Co., St Laurent, PQ, Canada). Volume exchange was performed over 10 min using a programmable ‘push-pull’ pump (PHD 2000; Harvard Apparatus, St Laurent, PQ, Canada). After completion of haemodilution, physiological measurements were recorded for an additional 60 min. The total duration of the experiment was 120 min. Brain temperature, brain tissue oxygen tension (PBrO2), CBF, brain temperature, MAP and heart rate (HR) were recorded with a computerized data acquisition system (DASYLab 5.6, Kent Scientific, Litchfield, CT, USA). Animals were sacrificed by anaesthetic overdose (ketamine 100 mg i.v.; Parke-Davis, Toronto, ON, Canada).
Statistical analysis
Data from both arms of the hippocampal or cerebral cortical groups were analysed by two-way ANOVA for each individual parameter (Sigma Stat Version 2.03S; Chicago, IL, USA). ABG and co-oximetry data were assessed before and after haemodilution (10 and 60 min). Other physiological measurements were assessed at three individual time points including the initial baseline (Baseline #1, 10 min), 10 min after saline or ß2 antagonist administration (Baseline #2, 40 min) and after haemodilution (Haemodilution, 100 min). Assessments were made for any time, arm or interaction effect for each measured parameter. A post hoc Tukey's test was utilized for post hoc pair-wise comparisons when a significant interaction effect was observed. Statistical significance was assessed at P<0.05. Data were presented as mean (SD). Laser Doppler flow values were normalized to the first baseline and reported as changes relative to Baseline #1 for each animal.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Co-oximetry and arterial blood gas analysis
At baseline, there were no significant differences between any co-oximetry or ABG measurement between the control and ß2 antagonist arms of the hippocampal or cerebral cortical groups. The baseline haemoglobin concentrations were near 125 g litre–1 and blood oxygen contents were near 7.5 mmol litre–1 for all arms (Table 1). After haemodilution, there was a significant reduction in haemoglobin concentration (63–71 g litre–1) and estimated blood oxygen content (3.7–4.2 mmol litre–1) compared with baseline for all arms (Table 1, P<0.001). There was also a small but consistent increase in methaemoglobin concentration by
0.3% in all arms after haemodilution (Table 1, P<0.001). There were no other significant differences in any other parameter after haemodilution (Table 1).
|
Haemodynamic and cerebral measurements
Heart rate
Initial baseline HRs (Baseline #1) were not statistically different between control and ß2 antagonist arms for either hippocampal or cerebral cortical groups (Fig. 1). After injection of the ß2 antagonist, the HR tended to be decreased in the ß2 antagonist arm of both hippocampal and cerebral cortical groups, relative to control arms. After haemodilution, there was an increase in HR in both arms of the hippocampal and cerebral cortical groups, relative to baseline (Fig. 1, P<0.015 and P<0.001, respectively). However, no significant interaction effect was observed for either group (P=0.221 and P=0.136, respectively).
|
Mean arterial pressure
At Baseline #1 (10 min), Baseline #2 (40 min) and after haemodilution (100 min) there were no differences in mean arterial pressure (MAP) between the control and ß2 antagonist arms in either the hippocampal or cerebral cortical groups (Fig. 1, P=0.234 and P=0.106, respectively). Upon administration of the ß2 antagonist, there was a transient decrease in MAP during drug administration (data not shown). The MAP then quickly returned to values near to the initial baseline (Fig. 1, 40 min). In the cerebral cortical group, there was a slight increase in MAP in both arms at 40 and 100 min, relative to Baseline #1 (P<0.05). This effect was not observed in the hippocampal group. No significant interaction effect was observed for the control and ß2 antagonist arms of either the hippocampal or cerebral cortical groups.
Cerebral temperature
The initial baseline hippocampal and cerebral cortical temperatures remained near 33–34°C in all study arms. In the hippocampal group, there was a significant time effect, with a tendency for temperature to be increased in both saline control and ß2 antagonist arms at 100 min after haemodilution (Fig. 2, P=0.047). No significant group or interaction effects were observed. In the cerebral cortical group, there was a significant time (P<0.001), arm (P=0.034) and interaction effect (P=0.027) when comparing the ß2 antagonist and saline control arms. Post hoc analysis demonstrates that the cerebral cortical temperature was significantly lower in the ß2 antagonist arm, relative to the saline control group, after haemodilution at 100 min (Fig. 3, P<0.05).
|
|
Cerebral tissue oxygen tension (PBrO2)
There was no significant change in hippocampal PBrO2 values between arms or over time throughout the duration of the experiment (Fig. 2). Baseline cerebral cortical PBrO2 [13.43 (7.49) torr] tended to be below that measured in the hippocampus [20.28 (2.20) torr]. However, there was no difference between baseline measurements of cerebral cortical PBrO2 in saline control or ß2 antagonist arms, either before (Baseline #1) or after ß2 antagonist administration (Baseline #2) (Fig. 3). No significant time (P=0.081) or arm effects (P=0.061) were observed for cerebral cortical PBrO2 measurements. However, a significant interaction effect was observed (P=0.004) demonstrating that cerebral cortical tissue oxygen tension was reduced in the ß2 antagonist arm [7.2 (2.0) torr] relative to the control arm [16.3 (6.4) torr] after haemodilution at 100 min (Fig. 3, P<0.05).
Normalized regional cerebral blood flow
In both the hippocampal and cerebral cortical groups, the regional cerebral blood flow (rCBF) remained stable over the initial baseline (Baseline #1) and after administration of ß2 antagonist or saline (Baseline #2) (Figs 2 and 3). In the hippocampal group, haemodilution resulted in a significant increase in rCBF in both ß2 antagonist and vehicle arms (Fig. 2, P<0.001). However, there was no difference between the control and ß2 antagonist arms within the hippocampal group at any time (Fig. 2, P=0.256). In contrast, significant time (P<0.001), arm (P=0.010) and interaction effects (P<0.001) were observed when comparing control and experimental arms in the cerebral cortical group. Post hoc analysis demonstrated that the relative cerebral cortical blood flow was lower in the ß2 antagonist arm [1.4 (0.2) relative to the saline control arm [1.7 (0.2)], after haemodilution at 100 min (Fig. 3, P<0.05).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The present study supports the hypothesis that ß2 adrenergic antagonism impairs parietal cerebral cortical oxygen delivery after acute haemodilution. In the ß2 antagonist treatment arm of the cerebral cortical group, cerebral temperature, tissue oxygen tension and rCBF were all significantly reduced relative to the control arm after haemodilution. These data suggest that the regional cerebral cortical oxygen delivery is maintained by mechanisms which rely upon activation of ß2 adrenoreceptors. Previous haemodilution studies have demonstrated that cerebral cortical oxygen tension was maintained at similar or lower haemoglobin concentrations, in part because of a regulated increase in CBF.8 9 19 Our data demonstrate that inhibition of cerebral vasodilatation results in reduced cerebral oxygen delivery under similar conditions. Therefore, ß2 adrenoreceptor mediated cerebral vasodilatation likely represents an important regulatory mechanism which acts to maintain adequate cerebral tissue oxygen tension within the cerebral cortex after acute haemodilution.
Interestingly, no effect of ß2 antagonism was observed in the region of the hippocampus. This suggests that ß2 mediated regulation of CBF may be restricted to specific brain regions. Indeed, regional differences in the CBF response to haemodilution have been reported.11 After severe haemodilution, a much larger absolute increase in blood flow was observed to the visual, auditory, parietal, sensory motor and frontal cortex, relative to that measured in the hippocampus.11 These regional differences in CBF response may explain why we observed a significant effect of ß2 blockade in the parietal cerebral cortex, but not in the hippocampus.
The systemic effect of ICI 118,551 on HR was similar in both groups of rats which received the drug. The HR in treated animals tended to be lower than controls, after ICI 118,551 administration. This trend was maintained throughout the duration of the experiment and is consistent with the observation that HR is under ß2 adrenergic regulation.21 22 After haemodilution, the HR increased comparably over time in the treatment and control arms of both groups, suggesting that ß2 blockade did not completely inhibit the chronotropic response to haemodilution.
There were no significant differences in MAP when comparing the ß2 antagonist and control arms for either hippocampal or cerebral cortical groups. However, there was a slight reduction in MAP (13%) in both ß2 antagonist treatment arms at 80 min after haemodilution. This could reflect a reduction in cardiac output in the treatment arms of both hippocampal and cerebral cortical groups. Although cardiac output was not measured in the study, previously published experimental studies did not demonstrate a significant impairment in the increase in cardiac output after haemodilution in animals treated with combined ß1 and ß2 antagonists.23 24 Furthermore, if a reduction in cardiac output was responsible for the observed changes in cerebral cortical blood flow and tissue oxygen tension, then a similar effect should have been observed within the ß2 antagonist treatment arm of the hippocampal group. Such a generalized effect was not observed suggesting that ß2 adrenergic blockade had a specific effect on the cerebral cortical vasculature. Therefore, systemic haemodynamic factors were not likely responsible for the observed region specific effect of ß2 blockade on parietal cerebral cortical blood flow and oxygen delivery.
Physiological studies have demonstrated that ß2 adrenoreceptors may preferentially mediate cerebral vasodilatation in order to re-direct blood flow to the brain in times of physiological stress.25 26 Severe haemodilution may represent such a stress. The well-characterized increase in CBF observed during acute haemodilution has been attributed to passive changes in blood rheology and active cerebral vasodilatation.10–12 However, the mechanisms by which cerebral vasodilatation occur have not been fully characterized. The current study has demonstrated that ß2 adrenoreceptors may participate in the regulation of cerebral cortical vasodilatation during severe haemodilution.
Previous experimental studies have provided evidence that the ß2 antagonist ICI 118,551 is capable of crossing the blood–brain barrier and can inhibit the regulated increase in CBF in response to nicotine administration.14 19 20 Therefore, potential sites of action of the ß2 adrenergic antagonist in the study include the vascular smooth muscle,26 27 vascular endothelium,28 cerebral neurons17 29 and astrocytes.30 Interestingly, NO can mediate cerebral vasodilation by both endothelial dependent and independent mechanisms.14 17 31 Endothelial dependent mechanisms include ß2 adrenoreceptor mediated up-regulation of endothelial nitric oxide synthase (eNOS) expression.31 Conversely, endothelial independent mechanisms may regulate CBF by ß2 adrenergic mediated release of NO from perivascular cerebral neurons.14 17 Additional experimental studies support the hypothesis that increased cerebral cortical neuronal nitric oxide synthase (nNOS) activity may mediate increases in CBF during haemodilution.10 32
Assessment of relative rCBF utilizing laser Doppler flow probes does not provide an absolute measurement of rCBF. However, laser Doppler has been reported to accurately reflect relative changes in CBF after haemodilution.9 Therefore, assessment of relative changes of CBF is valid in this model. Our measurements of hippocampal and parietal cerebral cortical tissue oxygen tension demonstrate a higher tissue oxygen tension in the hippocampus. These measurements are consistent with previously published values using similar methodology and may reflect regional heterogeneity in cerebral tissue oxygen tension and metabolism.9 33 34
The baseline cerebral cortical temperatures tended to be lower than those observed in the hippocampus, possibly because of the closer proximity of the cerebral cortex to the atmosphere. However, no differences were observed between the control and ß2 antagonist arms of the cerebral cortical group at baseline. Immediately after haemodilution with warm pentastarch (37°C), there was a significant increase in brain temperature in the control arms of both the hippocampal and cerebral cortical groups. The maximal temperature was achieved in both groups at about 80 min. The subsequent reduction in temperature may represent redistribution of heat of the infused pentasarch. In the ß2 antagonist arm of the hippocampal group, the increase in brain temperature was blunted but not prevented. However, no increase in brain temperature was observed in the ß2 antagonist arm of the cerebral cortical group. This supports the hypothesis that cerebral cortical vasodilatation was prevented by specific ß2 adrenergic blockade.
In conclusion, our data support the hypothesis that active ß2 mediated cerebral vasodilatation is important in regulating cerebral cortical oxygen delivery in anaesthetized rats after acute haemodilution. Further characterization of the physiological regulation of CBF during haemodilution may help to optimize the management of surgical patients who experience severe acute haemodilution.
|
Acknowledgments |
|---|
The authors acknowledge the excellent technical support provided by Rong Qu and Jianli Wang. Preliminary results have been presented at the International Anaesthesia Research Foundation meeting in Honolulu (2004). G.M.T.H. is the recipient of the Bristol-Myers Squibb-Canadian Anesthesiologists' Society Career Scientist Award. Research support was provided by the Canadian Anesthesiologists' Society, the Physicians' Services Incorporated Foundation and the St Michael's Hospital Department of Anaesthesia.
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
1 Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646–52[CrossRef][Web of Science][Medline]
2 Weiskopf RB, Toy P, Hopf HW, et al. Acute isovolemic anemia impairs central processing as determined by P300 latency. Clin Neurophysiol 2005; 116:1028–32[CrossRef][Web of Science][Medline]
3 Jonas RA, Wypij D, Roth SJ, et al. The influence of haemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003; 126:1765–74
4 Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ, Shah A. Adverse effects of low haematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003; 125:1438–50
5 Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM. Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002; 102:237–44[CrossRef][Web of Science][Medline]
6 Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet 1988; 1:727–9[CrossRef][Web of Science][Medline]
7 Homi HM, Yang H, Pearlstein RD, Grocott HP. Haemodilution during cardiopulmonary bypass increases cerebral infarct volume after middle cerebral artery occlusion in rats. Anesth Analg 2004; 99:974–81
8 van Bommel J, Trouwborst A, Schwarte L, Siegemund M, Ince C, Henny C. Intestinal and cerebral oxygenation during severe isovolemic haemodilution and subsequent hyperoxic ventilation in a pig model. Anesthesiology 2002; 97:660–70[CrossRef][Web of Science][Medline]
9 Shen H, Greene AS, Stein EA, Hudetz AG. Functional cerebral hyperemia is unaffected by isovolemic haemodilution. Anesthesiology 2002; 96:142–7[CrossRef][Web of Science][Medline]
10 Hudetz AG, Wood JD, Kampine JP. 7-Nitroindazole impedes erythrocyte flow response to isovolemic haemodilution in the cerebral capillary circulation. J Cereb Blood Flow Metab 2000; 20:220–4[CrossRef][Web of Science][Medline]
11 Rebel A, Lenz C, Krieter H, Waschke KF, Van Ackern K, Kuschinsky W. Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats. Am J Physiol Heart Circ Physiol 2001; 280:H2591–7
12 Todd MM, Wu B, Maktabi M, Hindman BJ, Warner DS. Cerebral blood flow and oxygen delivery during hypoxemia and haemodilution: role of arterial oxygen content. Am J Physiol 1994; 267:H2025–31[Medline]
13 Toda N, Tanaka T, Ayajiki K, Okamura T. Cerebral vasodilatation induced by stimulation of the pterygopalatine ganglion and greater petrosal nerve in anaesthetized monkeys. Neuroscience 2000; 96:393–8[CrossRef][Web of Science][Medline]
14 Uchida S, Kawashima K, Lee TJ. Nicotine-induced NO-mediated increase in cortical cerebral blood flow is blocked by beta2-adrenoceptor antagonists in the anaesthetized rats. Auton Neurosci 2002; 96:126–30[CrossRef][Web of Science][Medline]
15 Hayashi T, Katsumi Y, Mukai T, et al. Neuronal nitric oxide has a role as a perfusion regulator and a synaptic modulator in cerebellum but not in neocortex during somatosensory stimulation—an animal PET study. Neurosci Res 2002; 44:155–65[CrossRef][Web of Science][Medline]
16 Yang G, Zhang Y, Ross ME, Iadecola C. Attenuation of activity-induced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase. Am J Physiol 2003; 285:H298–304
17 Lee TJ, Zhang W, Sarwinski S. Presynaptic beta(2)-adrenoceptors mediate nicotine-induced NOergic neurogenic dilation in porcine basilar arteries. Am J Physiol Heart Circ Physiol 2000; 279:H808–16
18 Hare GMT, Qu R, Worrall JMA, et al. Beta2 adrenergic blockade inhibits cerebral hyperemia and reduces cerebral cortical oxygen tension following haemodilution in rats. Anesth Analg 2005; 100:S–60
19 O'Donnell JM. Pharmacological characterization of the discriminative stimulus effects of clenbuterol in rats. Pharmacol Biochem Behav 1997; 58:813–18[CrossRef][Web of Science][Medline]
20 Hallberg H and Almgren O. Modulation of oxotremorine-induced tremor by central beta-adrenoceptors. Acta Physiol Scand 1987; 129:407–13[Web of Science][Medline]
21 Gaiddon C, Larmet Y, Trinh E, Boutillier AL, Sommer B, Loeffler JP. Brain-derived neurotrophic factor exerts opposing effects on beta2-adrenergic receptor according to depolarization status of cerebellar neurons. J Neurochem 1999; 73:1467–76[CrossRef][Web of Science][Medline]
22 McConville P, Spencer RG, Lakatta EG. Temporal dynamics of inotropic, chronotropic, and metabolic responses during beta1- and beta2-AR stimulation in the isolated, perfused rat heart. Am J Physiol 2005; 289:E412–18
23 Clarke TN, Foex P, Roberts JG, Saner CA, Bennett MJ. Circulatory responses of the dog to acute isovolumic anaemia in the presence of high-grade adrenergic beta-receptor blockade. Br J Anaesth 1980; 52:337–41[Web of Science][Medline]
24 Nozaki J, Kitahata H, Tanaka K, Kawahito S, Oshita S. The effects of acute normovolemic haemodilution on left ventricular systolic and diastolic function in the absence or presence of beta-adrenergic blockade in dogs. Anesth Analg 2002; 94:1120–6
25 Chruscinski A, Brede ME, Meinel L, Lohse MJ, Kobilka BK, Hein L. Differential distribution of beta-adrenergic receptor subtypes in blood vessels of knockout mice lacking beta(1)- or beta(2)-adrenergic receptors. Mol Pharmacol 2001; 60:955–62
26 Chiba S and Tsukada M. Vascular responses to beta-adrenoceptor subtype-selective agonists with and without endothelium in rat common carotid arteries. J Auton Pharmacol 2001; 21:7–13[CrossRef][Web of Science][Medline]
27 Sun D, Huang A, Mital S, et al. Norepinephrine elicits beta2-receptor-mediated dilation of isolated human coronary arterioles. Circulation 2002; 106:550–5
28 Pottecher J, Cheisson G, Huet O, et al. Beta2-adrenergic agonist protects human endothelial cells from hypoxia/reoxygenation injury in vitro. Crit Care Med 2006; 34:165–72[CrossRef][Web of Science][Medline]
29 Hillman KL, Doze VA, Porter JE. Functional characterization of the beta-adrenergic receptor subtypes expressed by CA1 pyramidal cells in the rat hippocampus. J Pharmacol Exp Ther 2005; 314:561–7
30 Junker V, Becker A, Huhne R, et al. Stimulation of beta-adrenoceptors activates astrocytes and provides neuroprotection. Eur J Pharmacol 2002; 446:25–36[CrossRef][Web of Science][Medline]
31 Ferro A, Coash M, Yamamoto T, Rob J, Ji Y, Queen L. Nitric oxide-dependent beta2-adrenergic dilatation of rat aorta is mediated through activation of both protein kinase A and Akt. Br J Pharmacol 2004; 143:397–403[CrossRef][Web of Science][Medline]
32 Hare GMT, Mazer CD, Mak W, et al. Haemodilutional anemia is associated with increased cerebral neuronal nitric oxide synthase gene expression. J Appl Physiol 2003; 94:2058–67
33 Dunn JF, Nwaigwe CI, Roche M. Measurement of arterial, venous, and interstitial pO2 during acute hypoxia in rat brain using a time-resolved luminescence-based oxygen sensor. Adv Exp Med Biol 1999; 471:43–8[Web of Science][Medline]
34 Piantadosi CA, Zhang J, Demchenko IT. Production of hydroxyl radical in the hippocampus after CO hypoxia or hypoxic hypoxia in the rat. Free Radic Biol Med 1997; 22:725–32[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. M. T. Hare, A. K. Y. Tsui, A. T. McLaren, T. E. Ragoonanan, J. Yu, and C. D. Mazer Anemia and Cerebral Outcomes: Many Questions, Fewer Answers Anesth. Analg., October 1, 2008; 107(4): 1356 - 1370. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||