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Gastrodin Improved Baroreflex Sensitivity and Increased Gamma-Amino Butyric Acid Content in Brains without Decreasing Blood Pressure in Spontaneously Hypertensive Rats

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... Systolic BP (SBP), diastolic BP (DBP) values from every heart beat were determined online. The mean values of these parameters during 1 h before administration (from 12:00 PM to 13:00 PM) and 6 h after administration (from 13:00 to 19:00) for each rat were calculated by the BP recording system (MPA-HBBS; Shanghai Alcott Biotech Co, Ltd, Shanghai, China) as previously described [12][13][14]. All the higher doses of these five drugs have the similar efficacy on BP reduction (by about 20 mm Hg reduction of SBP). ...
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This study was designed to investigate the impact of representative antihypertensive drugs of 5 classes on the sexual function in male spontaneously hypertensive rats (SHR) at doses that achieved similar blood pressure (BP) reduction. The experiment was performed in 6 groups of male SHR. The dose are 20 μg/kg/day for clonidine, 3 mg/kg/day for enalapril, 20 mg/kg/day for atenolol, 2 mg/kg/day for amlodipine, and 10 mg/kg/day for dihydrochlorothiazide. SHR were treated for 3 months, and then the penile erection and sexual behavior were detected. After BP recording, SHR were killed to evaluate the organ-damage, weight of accessory sex organs and levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone in serum. Five drugs had the similar efficacy on BP reduction. All drugs except of enalapril, significantly prolonged the mount latency, and decreased the mount frequency (P<0.05). Clonidine also reduced the conception rate (45% vs. 80% in control group, P<0.05). Amlodipine and dihydrochlorothiazide significantly increased the testosterone level (0.79±0.30, 0.80±0.34 vs. 0.49±0.20 in control group, unit: ng/dl, P<0.05). Enalapril, atenolol and amlodipine also significantly decreased the BP variability (systolic, 8.2±2.5, 7.6±1.8, 8.9±2.0 vs. 12.2±3.8 in control group, unit: mm Hg). All these drugs significantly decreased the organ-damage (P<0.05). In conclusion, long-term treatment with 5 common antihypertensive drugs possessed obvious organ protection in SHR. Clonidine, atenolol, amlodipine and dihydrochlorothiazide, but not enalapril, impair sexual function.
... These previous results indicate that increased BP variability may reduce arterial distensibility and enhance arterial stiffness. Meanwhile, numerous studies demonstrate that BP variability is related with poor outcome in many cardio-cerebro-vascular diseases including stroke [33][34][35]. In addition, the present study further demonstrated the relationships between BP variability and aortic stiffness-determining components, particularly the aortic elastin concentration (a negative correlation) and the ratio of aortic collagen/elastin (a positive correlation). ...
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Ambulatory arterial stiffness index (AASI) has been proposed as a new measure of arterial stiffness for predicting cardio–cerebro–vascular morbidity and mortality. However, there has been no research on the direct relationships between AASI and arterial stiffness-determining factors. We utilized beat-to-beat intra-aortic blood pressure (BP) telemetry to characterize AASI in Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR). By determination of aortic structural components and analysis of their correlations with AASI, we provided the first direct evidence for the associations between AASI and arterial stiffness-determining factors including the collagen content and collagen/elastin. Ambulatory arterial stiffness index was positively correlated with pulse pressure in both WKY and SHR, less dependent on BP and BP variability than pulse pressure, and relatively stable, especially the number of BP readings not less than ~36. The correlations between AASI and aortic components were comparable for various AASI values derived from BP readings not less than ~36. Not only AASI but also BP variability and pulse pressure demonstrated a direct relationship with arterial stiffness. These findings indicate AASI may become a routine measure in human arterial stiffness assessment. It is recommended to use a cluster of parameters such as AASI, BP variability, and pulse pressure for evaluating arterial stiffness.
... Stabilizing blood pressure and enhancing arterial baroreflex function may become new strategies in prevention of stroke [20][21][22]. A variety of chemicals, such as clonidine, moxonidine, folic acid, mecobalamin [23], and gastrodin [24], could enhance arterial baroreflex function in rats. Previous studies also found ketanserin, a selective 5-HT 2 A receptor antagonist, could reduce the incidence of fetal stroke in SHR-SP through restoring the impaired BRS in SHR-SP [20]. ...
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To examine the effects of combination with levamlodipine and bisoprolol on stroke in rats. For acute study, Systolic blood pressure (SBP) and heart period (HP) were monitored in conscious stroke prone-spontaneously hypertensive rats (SHR-SP) and sinoaortic denervation (SAD) rats before and after intragastric administration of either drug at a single dose. Rats were subjected to middle cerebral arterial occlusion (MCAO) half an hour after drug administration; sacrificed 24 h later to measure the infarct size. For long-term study, drugs (either alone or in combination) were delivered via food to SHR-SP. The survival time was recorded. SBP was significantly reduced by combination therapy both in SHR-SP and SAD rats. Neutralization on heart rate (HR) was observed in combination. The drug combination increased baroreflex sensitivity (BRS) and reduced SBP variability (SBPV). In chronic experiments, the lifespan of SHR-SP rats exposed to the drug combination was longer than that in rats exposed to either drug alone. The infarct area was the smallest in subjects receiving drug combination in SD rats both with and without SAD. Combined use of levamlodipine and bisoprolol produced better protection against stroke.
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Objective: To study the correlation between the contents of gastrodin and polysaccharides with the variety of commercial specifications, grades, and cultivated areas of Gastrodia Tuber (Tianma), the tuber of Gastrodia elata, and then to choose the suitable chemical marker to assess the quality of Tianma raw materials. Methods: Gastrodin and polysaccharides were quantified in 35 Tianma samples including Winter Tianma which was harvested in winter, Spring Tianma which was harvested in spring with their different grades and cultivation areas by HPLC and spectrophotometry, respectively. Combined with the morphological characteristics, the correlation between the various Tianma samples with the amounts of gastrodin and polysaccharides was studied. Results: The content of polysaccharides in Winter Tianma (26.05%, n = 24) was higher than that in Spring Tianma (20.21%, n = 10). In contrast, the amount of gastrodin in Winter Tianma (0.49%, n = 24) was lower than that in Spring Tianma (0.68%, n = 10). Among Tianma samples with different grades, the content of polysaccharides in the first grade (32.65%, n = 6) and second grade (32.89%, n = 6) was higher than that in the third grade (21.71%, n = 8) and fourth grade samples (14.57%, n = 4). But, the amounts of gastrodin in the Tianma samples of the four grades were similar, which were 0.46% (n = 6), 0.65% (n = 6), 0.43% (n = 8), and 0.44% (n = 4) in the first, second, third, and fourth grade Tianma, respectively. Moreover, the contents of gastrodin and polysaccharides in Tianma samples collected from the famous cultivation regions such as Sichuan, Shaanxi, and Yunnan provinces of China were higher than those from others areas. Conclusion: The developed HPLC and spectrophotometry methods are accurate and reliable to assay the amounts of gastrodin and polysaccharides in Tianma. The amount of polysaccharides is related to the quality of Tianma samples authenticated by the commercial specifications, grades, and traditional experience, and therefore is a better marker to assess the quality of Tianma. ©, 2015, Editorial Office of Chinese Traditional and Herbal Drugs. All right reserved.
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Cardiac vagal preganglionic neurons (CVPN) are responsible for the tonic, reflex and respiratory modulation of heart rate (HR). Although CVPN receive GABAergic and glutamatergic inputs, likely involved in respiratory and reflex modulation of HR respectively, little else is known regarding the functions controlled by ionotropic inputs. Activation of g-protein coupled receptors (GPCR) alters these inputs, but the functional consequence is largely unknown. The present study aimed to delineate how ionotropic GABAergic, glycinergic and glutamatergic inputs contribute to the tonic and reflex control of HR and in particular determine which receptor subtypes were involved. Furthermore, we wished to establish how activation of the 5-HT1A GPCR affects tonic and reflex control of HR and what ionotropic interactions this might involve. Microinjection of the GABAA antagonist picrotoxin into CVPN decreased HR but did not affect baroreflex bradycardia. The glycine antagonist strychnine did not alter HR or baroreflex bradycardia. Combined microinjection of the NMDA antagonist, MK801, and AMPA antagonist, CNQX, into CVPN evoked a small bradycardia and abolished baroreflex bradycardia. MK801 attenuated whereas CNQX abolished baroreceptor bradycardia. Control intravenous injections of the 5-HT1A agonist 8-OH-DPAT evoked a small bradycardia and potentiated baroreflex bradycardia. These effects were still observed following microinjection of picrotoxin but not strychnine into CVPN. We conclude that activation of GABAA receptors set the level of HR whereas AMPA to a greater extent than NMDA receptors elicit baroreflex changes in HR. Furthermore, activation of 5-HT1A receptors evokes bradycardia and enhances baroreflex changes in HR due to interactions with glycinergic neurons involving strychnine receptors. This study provides reference for future studies investigating how diseases alter neurochemical inputs to CVPN.
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Inhibitory neurotransmission has an important role in the processing of sensory afferent signals in the nucleus of the solitary tract (NTS), particularly in spontaneously hypertensive rats (SHR). In the present study, we tested the hypothesis that γ-aminobutyric acid (GABA) mediated neurotransmission within the NTS produces an inhibition of the baroreflex response of splanchnic sympathetic nerve discharge (sSND). In urethane-anesthetized, artificially ventilated and vagotomized male SHR and Wistar Kyoto (WKY) rats we compared baroreflex-response curves evoked after bilateral injections into the NTS of the GABA-A antagonist bicuculline (25pmol/50nl) or the GABA-B antagonist CGP 35348 (5nmol/50nl). Baseline MAP in SHR was higher than the WKY rats (SHR: 153±5, vs. WKY: 112±6mm Hg, p<0.05). Bilateral injection of bicuculline or CGP 35348 into the NTS induced a transient (5min) reduction in MAP (∆=-26±4 and -41±6mm Hg, respectively vs. saline ∆=+4±3mmHg, p<0.05) and sSND (∆=-21±13 and -78±7%, respectively vs. saline: ∆=+6±4% p<0.05). Analysis of the baroreceptor curve revealed a decrease in the lower plateau (43±11 and 15±5%, respectively vs. saline: 78±6%, p<0.05) and an increase in the sympathetic gain of baroreflex (6.3±0.3, 7.2±0.8% respectively vs. saline: 4.2±0.4%, p<0.05). Bicuculline or CGP35348 into the NTS in WKY rats did not change MAP, sSND and sympathetic baroreflex gain. These data indicate that GABAergic mechanisms within the NTS act tonically reducing sympathetic baroreflex gain in SHR.
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The present study was designed to investigate the effects of low-dose ketanserin on BPV (blood pressure variability), BRS (baroreflex sensitivity) and organ damage in SHR (spontaneously hypertensive rats). Ketanserin was mixed in rat chow at an estimated dose of 0.1 mg.kg(-1) of body weight.day(-1). SHR were treated for 4 months. BP (blood pressure) was then recorded continuously for 24 h in a conscious state. After determination of BRS, rats were killed for organ damage evaluation. It was found that long-term treatment with low-dose ketanserin did not lower BP levels, but significantly decreased BPV, enhanced BRS and reduced organ damage in SHR. Multiple regression analysis showed that the decrease in left ventricular hypertrophy was most closely correlated (or associated) with the increase in BRS, whereas the decrease in aortic hypertrophy was most closely associated with the decrease in diastolic BPV and the amelioration in renal lesion, with the increase in BRS and the decrease in diastolic BPV. In conclusion, low-dose ketanserin produces organ protection independently of its BP-lowering action in SHR, and this organ protection was importantly attributable to the enhancement of BRS and decrease in BPV.
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The aim of this study was to explore the effect of gastrodin on the level of amino acids in the striatum in the rats of cerebral ischemia-reperfusion injury. 30 male SD rats were randomly divided into 3 groups: the group of pseudo-operation (normal control group, NC group), the group of cerebral ischemia-reperfusion injury (CIRI group), and the group of cerebral ischemia-reperfusion injury treated with gastrodin (G group). Cerebral ischemia-reperfusion injury was induced through middle cerebral artery occlusion (MCAO). 10 minutes before the operation, the rats in the G group were injected with gastrodin (50 mg/kg) intraperitoneally once. The rats in the CIRI and NC group were injected with the same volume of 10% propylene glycol normal saline intraperitoneally once. The levels of glutamic acid (Glu), aspartic acid (Asp), gamma-aminobutyric acid (GABA), taurine (Tau) in striatum in the rats of the 3 groups were measured with the method of microdialysis-HPLC techniques. The ratio of Glu to GABA was calculated. The volume of cerebral infarction was quantified. This study showed that gastrodin can decrease the volume of cerebral infarction, ameliorate the cerebral injury in the rats of cerebral ischemia-reperfusion. The mechanisms might be that gastrodin can improve the level of amino acids in striatum.
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An effective way to determine the amount of different neurotransmitters is vital to the study of brain function. Here, a highly sensitive HPLC-MS/MS method was developed to simultaneously measure γ-aminobutyric acid, dopamine, epinephrine, norepinepherine, glutamate and serotonin in one sample. The quantification of the neurotransmitters was achieved by a tandem mass spectrometer using the selected reaction monitoring scan mode. The method validation included selectivity, linearity, accuracy, precision, stability, recovery and matrix effect. For the six neurotransmitters, the linear regression analysis was calibrated by deuterated internal standards with a R(2) of over 0.991, and the limit of detection (LOD) and the limit of quantification (LOQ) were from 2.5 to 500 pg/mg and 7.5 to 1000 pg/mg, respectively. This method was employed here to reveal different types and amounts of neurotransmitters simultaneously in adult and embryonic rat brains. Here, the change of dopamine concentration in embryonic and adult brain was from 0.071 to 0.760 ng/mg of brain tissue, GABA was from 207.643 to 445.148 ng/mg, glutamate was from 679.535 to 1408.920 ng/mg, serotonin was from 0.058 to 0.485 ng/mg and norepinepherine was from 0.054 to 0.290 ng/mg. For epinephrine, it was only detected in embryonic stage but not in adult, with the concentration at 0.241 ng/mg.
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In prior studies, we found that activation of cannabinoid-1 receptors in the nucleus tractus solitarii (NTS) prolonged baroreflex-induced sympathoinhibition in rats. In many regions of the central nervous system, activation of cannabinoid-1 receptors presynaptically inhibits γ-aminobutyric acid (GABA) release, disinhibiting postsynaptic neurons. To determine if cannabinoid-1 receptor-mediated presynaptic inhibition of GABA release occurs in the NTS, we recorded miniature inhibitory postsynaptic currents in anatomically identified second-order baroreceptive NTS neurons in the presence of ionotropic glutamate receptor antagonists and tetrodotoxin. The cannabinoid-1 receptor agonists, WIN 55212-2 (0.3-30 μM) and methanandamide (3 μM) decreased the frequency of miniature inhibitory postsynaptic currents in a concentration-dependent manner, an effect that was blocked by the cannabinoid-1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251, 5 μM). Importantly, depolarization of second-order baroreceptive neurons decreased the frequency of miniature inhibitory postsynaptic currents; an effect which was blocked by the cannabinoid-1 receptor antagonist. The data indicate that depolarization of second-order baroreceptive NTS neurons induces endocannabinoid release from the neurons, leading to activation of presynaptic cannabinoid-1 receptors, inhibition of GABA release and subsequent enhanced baroreflex signaling in the NTS. The data suggest that endocannabinoid signaling in the NTS regulates short-term synaptic plasticity and provide a mechanism for endocannabinoid modulation of central baroreflex control.
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To study the roles of N-methyl-D-aspartate (NMDA) receptors in arterial baroreflex. Experiments were performed in 17 urethane-anaesthetized male Sprague-Dawly rats. Twenty-seven rostral ventrolateral medulla (RVLM) neurons were electrophysiologically identified as putative presympathetic neurons. Responses of these neurons to baroreflex activation were used as an index to observe the effects of 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) microinjected (0.1 microL, 50 mmol.L-1) into the nucleus tractus solitarii (NTS) or the caudal ventrolateral medulla (CVLM) ipsilaterally. In the NTS, CPP eliminated or attenuated the inhibition of these neurons induced by aortic nerve stimulation, but the inhibition induced by elevation of arterial pressure was not eliminated and the cardiac cycle-related rhythm of spontaneous discharge still existed. Whereas in the CVLM, CPP eliminated not only the inhibition of these neurons induced by aortic nerve stimulation, but the inhibition induced by blood pressure elevation and the cardiac cycle-related rhythm of spontaneous discharge disappeared. NMDA mechanism is importantly involved in the mechanism of baroreflex both in the NTS and in the CVLM; the barosensitive neurons in the NTS project to ipsilateral CVLM.
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Gastrodin is one of the natural compound isolated from Gastrodia elata and has known anticonvulsant effects, although the exact pharmacological principles of this natural compound and its effects on other aspects of gamma-aminobutyric acid (GABA) metabolism in vivo have not been explored. Therefore, in the present study, the effects of gastrodin on GABA metabolism in the gerbil hippocampus were examined, in an effort to identify the antiepileptic characteristics of this substance. Gastrodin reduced the seizure score in the treated group, although the immunoreactivities of GABA synthetic enzymes and GABA transporters were unaltered in gastrodin-treated animals. Interestingly, in the gastrodin-treated group, GABA transaminase (GABA-T) immunoreactivity in the hippocampus, particularly in neurons, was significantly decreased. In the gastrodin-treated group, both succinic semialdehyde dehydrogenase (SSADH) and succinic semialdehyde reductase (SSAR) immunoreactivities in the hippocampus was also decreased significantly, which stood in contrast to the nontreated group, in which strong SSADH and SSAR immunoreactivities were detected. From the neuroanatomical viewpoint, these findings suggest that gastrodin may cause the elevation of GABA concentration by inhibiting the GABA shunt.
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Arterial baroreflex is one of the most important mechanisms in the regulation of cardiovascular activities. Arterial baroreflex function can be expressed as baroreflex sensitivity (BRS). The present study was designed to test 2 hypotheses: (1) BRS is a new independent predictor for the incidence of stroke in hypertension, and (2) restoration of BRS can prevent stroke in hypertension. First, 82 stroke-prone spontaneously hypertensive rats (SHR-SP) aged 28 to 30 weeks were used. After measuring blood pressure and BRS, the survival time was observed. Second, 12 SHR-SP aged 8 months were used. Blood pressure and BRS were determined separately before and after intragastric administration of ketanserin (0.3 and 3.0 mg/kg). Third, SHR-SP aged 5 months were treated with ketanserin for 12 weeks (0.3 mg and 3.0 mg/kg per day). At the end of the treatment, blood pressure and BRS were determined and the end-organ damage was evaluated. Last, SHR-SP aged 3 months were treated with ketanserin (0.3 and 3.0 mg/kg per day) for life and the survival time was recorded. Stroke was significantly delayed in rats with high BRS than those with low BRS (time to 50% death was 1.47-fold longer than low BRS group; P<0.01). Ketanserin of 3.0 mg/kg per day decreased blood pressure and enhanced BRS, whereas 0.3 mg/kg per day only enhanced the BRS. Fatal stroke incidences were markedly reduced by treatment with both doses (P<0.0001 versus control group). The present study provides evidence that BRS is an independent predictor for stroke in hypertension. Restoration of BRS may be a new strategy for the prevention of stroke.
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The phenolic glucoside gastrodin is the main component extracted from the rhizome of Gastrodia elata (Orchidaceae), a Chinese herbal medicine, which has long been used for treating dizziness, epilepsy, stroke and dementia. The present study aims to investigate the effect of gastrodin on hypoxia-induced neurotoxicity in cultured rat cortical neurons. Neuron survival and extracellular glutamate level were measured after an insult by hypoxia. Glutamate concentrations were determined by an HPLC-ECD system. The results demonstrated that neurons were significantly damaged by hypoxia for 24 h. When pretreated with gastrodin (100, 200 μg/mL) in hypoxia, neuron survival was significantly increased compared with no gastrodin treatment. Moreover, the enhancement of extracellular glutamate level stimulated by hypoxia was inhibited by pretreatment with gastrodin (100 μg/mL). Further studies demonstrated that gastrodin prevented glutamate- and NMDA-induced neurotoxicity. In addition, gastrodin also inhibited the extracellular glutamate level induced by NMDA insult. These findings suggest that gastrodin has a neuroprotective action against hypoxia in the cultured cortical neuron, and the mechanism may involve a decreasing of the extracellular glutamate level. Abbreviations GABA:γ-aminobutyric acid DMEM:Dulbecco's modified Eagle's medium MTT:3-(4,5)-dimethylthiathiazo(-z-yl)-3,5-di-phenytetrazoliumromide HPLC-ECD:high performance liquid chromatography with electrochemical detection
Protective effects of gastrodin on hypoxia-induced toxicity in
  • X Zeng
  • S Zhang
  • L Zhang
  • K Zhang
  • Zheng
Zeng X, Zhang S, Zhang L, Zhang K, Zheng X. Protective effects of gastrodin on hypoxia-induced toxicity in