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NEUROSURGICAL ANESTHESIOLOGY AND NEUROSCIENCE

The Effects of β-Adrenoceptor Antagonists on Proinflammatory Cytokine Concentrations After Subarachnoid Hemorrhage in Rats

From the Department of Anesthesiology, Nara Medical University, Kashihara City, Nara, Japan.

Address correspondence and reprint requests to Haruto Kato, MD, Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara 634-8522, Japan. Address e-mail to hkato{at}naramed-u.ac.jp.

Abstract

BACKGROUND: Proinflammatory cytokines increase in cerebrospinal fluid (CSF) after subarachnoid hemorrhage (SAH). Recent evidence suggested that β-adrenoceptor antagonist could reduce proinflammatory cytokines. We conducted the present study to examine whether β-adrenoceptor antagonists would reduce proinflammatory cytokine concentrations after SAH in rats.

METHODS: In Experiment 1, to investigate the time course of interleukin-6 (IL-6) and tumor necrosis factor- (TNF-), rats were randomized into groups: 1, 3, 6, and 12 h after SAH or sham operation. CSF and blood samples were obtained at each time point. In Experiment 2, to investigate the effects of β-adrenoceptor antagonists on the IL-6 and TNF- concentrations, rats were randomized into groups: 1) control group: SAH + normal saline, 2) propranolol group: SAH + propranolol, 3) metoprolol group: SAH + metoprolol, and 4) butoxamine group: SAH + butoxamine (β₂-adrenoceptor antagonist). CSF and blood samples were obtained 6 h after SAH. IL-6 and TNF- concentrations in samples were measured.

RESULTS: In Experiment 1, CSF IL-6 concentrations in the SAH groups increased markedly and peaked at 6 h after SAH, whereas CSF TNF- concentrations in the SAH groups were consistently low. In Experiment 2, CSF IL-6 concentrations in the propranolol and butoxamine groups were significantly lower compared with those in the control group (P < 0.01 and P < 0.05 for each group). Plasma IL-6, CSF TNF-, and plasma TNF- concentrations were comparable in all four groups.

CONCLUSIONS: CSF IL-6 concentrations increased in the acute stage of SAH and β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action suppressed this elevation of IL-6 concentrations after SAH in rats.

Subarachnoid hemorrhage (SAH) induces an inflammatory response and proinflammatory cytokines increase in the cerebrospinal fluid (CSF) and plasma in patients with SAH. The increase of proinflammatory cytokines in CSF has been suggested to contribute to the occurrence of delayed cerebral vasospasm and brain damage after SAH.1,2 In addition, SAH evokes a massive release of cathecholamines causing specific myocardial lesions and neurogenic pulmonary edema.3 Activation of β-adrenergic receptors has been indicated to be related to the production of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor- (TNF-). Norepinephrine was reported to induce IL-6 expression in astrocyte by the activation of β-adrenergic receptors.4 In patients with dilated cardiomyopathy, β-adrenoceptor antagonists inhibited increases of serum IL-6 and TNF- concentrations and improved left ventricular systolic function.5,6 However, the effects of β-adrenoceptor antagonists on proinflammatory cytokine concentrations after SAH have not been clarified. The present study was therefore conducted to test the hypothesis that the administration of a β-adrenoceptor antagonist may reduce the concentrations of proinflammatory cytokines IL-6 and TNF- after SAH in rats.

METHODS

All experimental protocols were approved by the Animal Care and Use Committee of Nara Medical University. Male Sprague-Dawley rats (Japan SLC, Shizuoka, Japan), weighing 400–500 g, were prevented from eating but allowed free access to water for 12 h before the experiment.

Anesthesia and Catheterization
Rats were anesthetized with 5% isoflurane in 100% oxygen. The trachea was intubated and the lungs were ventilated mechanically with a gas mixture of oxygen and air for Fio₂ 0.4. The isoflurane concentration was reduced by 2.0%. The arterial blood gases were kept within the physiological range. The rectal body temperature was maintained at 37.5°C ± 0.3°C by surface heating and cooling before SAH. The tail artery was cannulated with a polyethylene tube (SP-45) to monitor mean arterial blood pressure (MAP) and to obtain blood samples. The rats were placed in a stereotactic frame with the mouthpiece at 0 degrees.

Induction of Experimental SAH
The prechiasmatic SAH model was established according to the techniques described by Prunell et al.7 A needle with a rounded tip and a side hole (Withcare spinal set, 0.41 x 90 mm; Becton Dickinson, Madrid, Spain) was stereotactically inserted into the prechiasmatic cistern. The needle was tilted 30 degrees anteriorly and placed 7.5 mm anterior to bregma in the midline, with the hole facing the right side. The needle was lowered until the tip reached the skull base 2–3 mm anterior to the chiasma, approximately 10 mm from the brain surface. The burr hole was plugged with bone wax before insertion of the needle. SAH was induced by an injection of 200 µL of autologous arterial blood. The infusion was performed over a 3-min period to attenuate the steep elevation of intracranial pressure. Animals without the injection of blood were used as the sham operation group. Anesthesia was stopped 45 min after SAH or sham operation and the rats were allowed to recover.

Experiment 1: Time Course of IL-6 and TNF- Concentrations After SAH
Rats were assigned randomly to eight groups: 1) 1 h, 2) 3 h, 3) 6 h, and 4) 12 h after SAH; and 5) 1 h, 6) 3 h, 7) 6 h, and 8) 12 h after sham operation, CSF and blood samples were obtained. CSF samples were obtained through needle puncture of the cisterna magna and blood samples were obtained from the tail artery under anesthesia for measurement of proinflammatory cytokines IL-6 and TNF-. CSF and blood samples were immediately centrifuged (12,000 rpm, 10 min and 3500 rpm, 10 min, respectively). These supernatants were collected and stored at –80°C until assayed. Physiologic variables (heart rate, MAP, and rectal body temperature) were recorded before and until 30 min after SAH or sham operation.

Experimental 2: Effects of β-Adrenoceptor Antagonists on IL-6 and TNF- Concentrations
Rats were randomly assigned to 4 groups: 1) control group: SAH + normal saline (2 mL/kg), 2) propranolol group: SAH + propranolol (nonselective β-adrenoceptor antagonist, 10 mg/kg), 3) metoprolol group: SAH + metoprolol (selective β₁-adrenoceptor antagonist, 20 mg/kg), and 4) butoxamine group: SAH + butoxamine (selective β₂-adrenoceptor antagonist, 20 mg/kg). Each β-adrenoceptor antagonist and normal saline was administered intraperitoneally 5 min before the induction of SAH. Six hours after SAH, CSF and blood samples were obtained in each group under anesthesia for measurement of IL-6 and TNF- and immediately centrifuged. These supernatants were collected and stored at –80°C until assayed. Physiologic variables (heart rate, MAP, and rectal body temperature) were recorded before and until 30 min after SAH.

Measurements of IL-6 and TNF- Concentrations
The measurements of IL-6 concentration in CSF and plasma were performed using commercial rat enzyme-linked immunosorbent assay kits (Endogen, Rockford, IL), according to the manufacturers instructions. Briefly, after anti-rat IL-6 precoated 96-well strip plates were washed and 50 µL of sample diluent was added to each well, 50 µL of samples or standard (lyophilized recombinant rat IL-6, 0–2000 pg/mL) were added in duplicate and diluted into the plate, which was incubated for 2 h at 20°C–25°C. After being washed again, 100 µL of biotinylated antibody reagent was added to each well and plate and was incubated for 1 h at 20°C–25°C. The plate was washed, and 100 µL of streptavidin-horse radish peroxidase solution was added to each well. After 30 min of incubation at 20°C–25°C and a wash, 100 µL of premixed 3,3`,5,5`-tetramethylbenzidine substrate solution was added to each well. After 30 min of developing the plate in the dark at 20°C–25°C, the reaction was terminated by the addition of 100 µL of 0.18 M sulfuric acid to each well.

The measurements of TNF- concentration in CSF and plasma were performed using commercial rat enzyme-linked immunosorbent assay kits (Endogen), according to the manufacturers instructions. Briefly, after anti-rat TNF- precoated 96-well strip plates were washed and 50 µL of pretreatment buffer was added to each well, 50 µL of samples (samples were diluted 1:1 by adding standard diluent before testing) or standard (lyophilized recombinant rat TNF-, 0–2500 pg/mL) were added in duplicate and diluted into the plate, which was incubated for 1 h at 20°C–25°C. After being washed again, 100 µL of biotinylated antibody reagent was added to each well and plate and was incubated for 1 h at 20°C–25°C. The plate was washed, and 100 µL of streptavidin-HRP reagent was added to each well. After 30 min of incubation at 20°C–25°C and a wash, 100 µL of TMB substrate solution was added to each well. After 10 min of developing the plate in the dark at 20°C–25°C, the reaction was terminated by the addition of 100 µL of 0.18 M sulfuric acid to each well.

The absorbance was measured at 450 nm minus 550 nm using a microtiter plate reader (Multiskan MS, Labsystems, Helsinki, Finland). The absorbance of the standards against the standard concentration was analyzed on a statistical software StatView (SAS Institute, Cary, NC) and the standard curve was constructed. The detection levels for the assays were IL-6 <31 pg/mL and TNF- <31 pg/mL.

Statistical Analysis
IL-6 and TNF- concentrations were compared with the Kruskal–Wallis test, and if significant differences were found, then followed by the Mann–Whitney U rank-sum test with the Bonferroni correction. Physiologic variables were compared in each group with repeated-measures one-way analysis of variance followed by the Fishers least significant difference test and among groups with repeated-measures analysis of variance. If any significant differences were found, comparisons at each measurement times were made by one-way analysis of variance followed by the Fishers least significant difference test. Statistical significance was accepted at P < 0.05.

RESULTS

Time Course of IL-6 and TNF- Concentrations After SAH
Physiologic values are reported in Table 1. Arterial Pco₂, Po₂, glucose, MAP, and heart rate were similar in each group and among groups throughout the monitoring period.

The time course of IL-6 concentrations is reported in Figure 1. CSF IL-6 concentrations in SAH groups increased significantly and peaked at 6 h after SAH, whereas CSF IL-6 in the sham operation groups was not detectable. Plasma IL-6 concentrations in the SAH groups were significantly higher than those in the sham operation groups at 1, 3, and 6 h after SAH. The elevation of plasma IL-6 concentrations in the sham operation groups was not significant.

View larger version (19K): [in this window] [in a new window]   Figure 1. Time course of interleukin-6 (IL-6) concentrations in cerebrospinal fluid (CSF) (A) and plasma (B) after subarachnoid hemorrhage (SAH) or sham operation. CSF IL-6 concentrations peaked at 6 h after SAH, whereas those after sham operation were not detectable. Plasma IL-6 concentrations in SAH groups peaked at 1 h after SAH and were significantly larger than those in sham operation groups until 6 h after SAH. BD = below detection. Values are presented as mean ± sd. *P < 0.05 compared with sham.

The time course of TNF- concentrations is reported in Figure 2. CSF TNF- concentrations in the SAH groups increased slightly at 1 h after SAH and thereafter decreased gradually. CSF TNF- in the sham operation groups was not detectable. Plasma TNF- concentrations significantly increased and peaked at 1 h after SAH and sham operation and those in the SAH group were significantly higher compared with those in the sham operation group at 3 h after SAH.

View larger version (18K): [in this window] [in a new window]   Figure 2. Time course of tumor necrosis factor- (TNF-) concentrations in cerebrospinal fluid (CSF) (A) and plasma (B) after subarachnoid hemorrhage (SAH). CSF TNF- concentrations in SAH groups increased slightly and were significantly larger than those in sham operation groups at 1 h after SAH. In sham operation groups, CSF TNF- was not detectable. Plasma TNF- concentrations peaked at 1 h after SAH and sham operation, thereafter disappeared by 12 h after SAH and sham operation. Plasma TNF- concentrations in SAH groups were significantly larger than those in sham operation groups at 3 h after SAH. BD = below detection. Values are presented as mean ± sd. *P < 0.05 compared with sham.

Effects of β-Adrenoceptor Antagonists on IL-6 and TNF- Concentrations
Physiologic values are reported in Table 2. MAP was significantly lower compared with the control group in the propranolol group before and 5, 10, 20, and 30 min after SAH and in the metoprolol group 20 min after SAH. Heart rate was significantly slower compared with the control group in the propranplol, metoprolol, and butoxamine groups before and 5, 10, 20, and 30 min after SAH. Arterial Pco₂, Po₂, and glucose were similar in each group and among groups at the measurement time points.

The effects of β-adrenoceptor antagonists on the concentrations of IL-6 and TNF- at 6 h after SAH are reported in Figure 3. In the propranolol and butoxamine groups, CSF IL-6 concentrations were significantly lower compared with those in the control group (P = 0.0019 and P = 0.0072 for each group). Plasma IL-6, CSF TNF-, and plasma TNF- concentrations were comparable in all four groups.

View larger version (18K): [in this window] [in a new window]   Figure 3. Concentrations of cerebrospinal fluid (CSF) interleukin-6 (IL-6) (A), plasma IL-6 (B), CSF tumor necrosis factor- (TNF-) (C), and plasma TNF- (D) at 6 h after subarachnoid hemorrhage (SAH). Rats were randomized into four groups: 1) control group: SAH + normal saline (2 mL/kg), 2) propranolol group: SAH + propranolol (nonselective β-adrenoceptor antagonist, 10 mg/kg), 3) metoprolol group: SAH + metoprolol (selective β1-adrenoceptor antagonist, 20 mg/kg), and 4) butoxamine group: SAH + butoxamine (selective β2-adrenoceptor antagonist, 20 mg/kg). CSF IL-6 concentrations in the propranolol and butxamine groups were significantly lower than those in the control group. Plasma IL-6, CSF TNF-, and plasma TNF- concentrations were similar in all four groups. Values are presented as mean ± sd. *P < 0.01, P < 0.05 compared with control.

DISCUSSION

The results of the present study offer two major findings. First, CSF IL-6 concentrations increased markedly and peaked at 6 h after SAH, whereas CSF TNF- concentrations were slightly increased after SAH. Second, the administration of β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action significantly suppressed the increase of CSF IL-6 concentrations at 6 h after SAH.

Three experimental SAH models have been reported in rats. SAH in those models is induced via 1) intracranial endovascular perforation (perforation SAH model), 2) blood injection into the cisterna magna (cisterna magna SAH model), or 3) blood injection into the prechiasmatic cistern (prechiasmatic SAH model). The prechiasmatic SAH model has been demonstrated to be the most suitable for study of the sequelae after SAH, because it produces a significant decrease in cerebral blood flow, an acceptable mortality rate, and substantial pathological lesions, with high reproducibility.8 Therefore, we used the prechiasmatic SAH model in the present study.

CSF IL-6 concentrations increased markedly after SAH, although CSF TNF- concentrations were at lower levels throughout the study period. The peak concentrations of CSF IL-6 were much higher than those of plasma IL-6 after SAH, suggesting that CSF IL-6 was secreted, not only by vascular endothelial cells and blood cells, but also by the central nervous system. The time lag of the peak of IL-6 concentrations between plasma and CSF after SAH may be due to the time required for neutrophils and monocytes to secrete IL-6 infiltrate into the central nervous system. The peak concentrations of CSF IL-6 in the present study were similar or higher compared with the peak concentration of CSF IL-6 in patients with vasospasm after SAH.1,9 In patients with SAH, there was an impressive release of IL-6 to cisternal CSF in the early stage of SAH and an early significant increase of IL-6 might be predictive for the development of symptomatic cerebral vasospasm.9 CSF IL-6 concentrations were observed to be significantly increased only in the acute phase after SAH in patients with a poor clinical condition, and in whom delayed cerebral vasospasm and cerebral ischemia developed later.1 In an experimental study, intracisternal injection of IL-6 was demonstrated to induce long-lasting cerebral vasoconstriction in five of eight dogs.10

There is a lack of agreement in the literature regarding CSF TNF- concentrations after SAH. Some reports have shown that CSF TNF- was not detectable after SAH,11,12 whereas others have shown that CSF TNF- concentrations increased in SAH patients with unfavorable outcomes2 or CSF TNF- concentrations were comparable with serum TNF- concentrations after SAH.13 In the present study, CSF TNF- concentrations were consistently low and the peak concentration of CSF TNF- was lower than that of plasma TNF- after SAH. This finding suggests that CSF TNF- does not play a principal role in the initial inflammatory response in the central nervous system after SAH.

We next found that the administration of β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action significantly suppressed the increase in CSF IL-6 concentrations at 6 h after SAH. Propranolol, metoprolol, and butoxamine used in this study are all lipophilic, and therefore capable of crossing the blood–brain barrier. In SAH patients receiving β-adrenoreceptor antagonists, approximate brain/plasma concentration ratios of propranolol and metoprolol have been 26 and 12, respectively.14 Similar to results in the present study, several studies have reported that β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action can reduce IL-6 production. In patients with dilated cardiomyopathy, carvedilol (nonselective β-adrenoceptor antagonist with an ₁-adrenoceptor blocking action and antioxidant properties) reduced the elevation of circulating IL-6 concentrations,5,6 whereas motoprolol did not influence the elevated serum IL-6 concentrations.5 In rats with an acute myocardial infarction, carvedilol similarly reduced the elevation of cardiac IL-6 levels,15 whereas metoprolol did not affect the high cardiac IL-6 levels.16 In rats, propranolol and IL-10 blocked IL-1β-induced IL-6 release into the CSF and decreased IL-1β-triggered gliosis.17 In in vitro experiments, several studies have shown that production of IL-6 is increased by stimulation of β₂-adrenoceptors. Norepinephrine induced production and secretion of IL-6 from rat astrocytes in a dose-dependent manner, which was predominately mediated by β₂-adrenoceptors.4,18 In experimental traumatic brain injury in rats, norepinephrine infusion increased IL-6 concentrations in plasma and CSF.19 Christensen et al.20 reported that adrenaline increased the IL-6 release from murine pituicytes in a dose-dependent manner and propranolol and β₂-adrenoceptor antagonist completely blocked the effect of the adrenaline, whereas the β₁-adrenoceptor antagonist atenolol was inactive. Therefore, they indicated that the stimulatory effect of adrenaline on IL-6 release was mediated via β₂-adrenoceptors.

Some studies have proposed that IL-6 production is tissue specific and the effects of β₂-adrenoceptor antagonist on IL-6 production may therefore vary by tissue. Epinephrine infusion in rats increased IL-6 protein and mRNA in skeletal muscle but not in liver, and either propranolol or β₂-adrenoceptor antagonist inhibited epinephrine, but not lipopolysaccharide (LPS)-induced IL-6 synthesis.21 Nakamura et al.22 observed that administration of β₂-adrenoceptor agonist increased IL-6 mRNA expressions in whole kidney and renal medulla, but inhibited IL-6 mRNA expression in plasma, spleen, and thymus after LPS-induced endotoxaemia in rats. Furthermore, Nakamura et al.23 reported that β₂-adrenoceptor agonist at high concentrations significantly up-regulated IL-6 production, whereas at lower concentrations it down-regulated IL-6 production in renal resident macrophage cells exposed to LPS, which suggests a biphasic effect of β₂-adrenoceptor agonist on IL-6 production. Therefore, the action of β₂-adrenoceptor stimulation on IL-6 production is quite complex and controversial, and may be influenced by kinds of species, tissue, cell, and IL-6 production stimulant and by a degree of β₂-adrenoceptor activation.

The exact mechanisms in which β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action suppressed CSF IL-6 concentrations after SAH are unclear. However, previous studies have demonstrated several signaling pathways for β₂-adrenoceptor stimulation-induced IL-6 production. Yin et al.24 reported that noncanonical cyclic adenosine monophosphate pathway and p38 mitogen-activated protein kinase pathway mediated β₂-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts. Frost et al.21 demonstrated that epinephrine induced IL-6 expression in muscle cells in a dose- and time-dependent manner, and the epinephrine-induced IL-6 expression was blocked by propranolol, β₂-adrenoceptor antagonist, c-Jun NH₂-terminal kinase inhibitor, p38 mitogen-activated protein kinase inhibitor, and histone deacetylase inhibitor. However, further study would be required to clarify the exact mechanisms.

Several studies have reported that β-adrenoceptor antagonists have an inhibitory action on TNF- production. Carvedilol and metoprolol suppressed serum TNF- concentrations in patients with idiopathic dilated cardiomyopathy.5 In rats with acute myocardial infarction, myocardial TNF- expressions were reduced by the administrations of carvedilol15 and metoprolol.16 However, these reports were related to cardiac disease. Therefore, the effect of β-adrenoceptor antagonists on reduction of TNF- production might depend on their effect on reduction of cardiac load.

In the present study, β-adrenoceptor antagonists did not influence the plasma and CSF TNF- concentrations at 6 h after SAH. The reason why this finding was inconsistent with findings of the other studies might involve differences in species, tissues, cells, and stimulant of TNF- production or because TNF- production in plasma and CSF at 6 h after SAH was too low to ensure the influence of β-adrenoceptor antagonists.

Our study has several limitations. First, the CSF volume obtained after SAH was so small that we could not measure the other proinflammatory cytokines and anti-inflammatory cytokines. Therefore, the influence of β-adrenoceptor antagonists on the other proinflammatory cytokines and anti-inflammatory cytokines after SAH is unclear. However, we selected IL-6 and TNF- which have been suggested to contribute to the occurrence of delayed cerebral vasospasm or brain damage after SAH in previous studies.1,2,9,10 Second, since we studied β-adrenoceptor antagonists at a single dose, dose-dependent effects were unclear. However, in the present study, we used the dosage of each β- adrenoceptor antagonist, which was as much as dosage commonly used in a rat model and did not induce excessive hypotension.25–27 Administration of the higher dosage of β-adrenoceptor antagonists might lead to excessive hypotension and bronchospasm, which could influence the production of IL-6 and TNF-. Additional experiments are necessary to address these issues. Third, in the present study, the effects of β-adrenoceptor antagonists with a β₂-adrenoceptor blocking action on cerebral blood flow and functional outcome, such as mortality or cerebral vasospasm after SAH, are unclear. Further experiments are needed to evaluate whether the effects of β-adrenoceptor antagonists with a β₂-aderenoceptor blocking action on IL-6 concentrations are biologically or clinically significant.

In conclusion, we investigated the time course of proinflammatory cytokines IL-6 and TNF- after SAH and the effects of β-adrenoceptor antagonists on IL-6 and TNF- concentrations in rats. The results indicated that CSF IL-6 concentrations increased in the acute stage of SAH, although CSF TNF- concentrations were at lower levels. In addition, β-adrenoceptor antagonists with a β₂-aderenoceptor blocking action possessed the ability to inhibit the increase of CSF IL-6 concentrations after SAH. The results of the present study may provide the key to development of strategies to regulate the initial excessive inflammatory response after SAH.

Footnotes

Accepted for publication July 18, 2008.

Supported by departmental source.

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