Decreased postnatal neurogenesis in the hippocampus combined with stress experience during adolescence is accompanied by an enhanced incidence of behavioral pathologies in adult mice

Background

Although long-term potentiation (LTP) of synaptic strength is very persistent, current studies have provided evidence that various manipulations or pharmacological treatment when applied shortly after LTP induction can reverse it. This kind of reversal of synaptic strength is termed as depotentiation and may have a function to increase the flexibility and storage capacity of neuronal networks. Our previous studies have demonstrated that an increase in extracellular levels of adenosine and subsequent activation of adenosine A₁ receptors are important for the induction of depotentiation; however, the signaling downstream of adenosine A₁ receptors to mediate depotentiation induction remains elusive.

Results

We confirm that depotentiation induced by low-frequency stimulation (LFS) (2 Hz, 10 min, 1200 pulses) was dependent on adenosine A₁ receptor activation, because it was mimicked by bath-applied adenosine A₁ receptor agonist N ⁶-cyclopentyladenosine (CPA) and was inhibited by the selective adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Pretreatment of the hippocampal slices with the selective p38 mitogen-activated protein kinase (MAPK) inhibitors, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl]-5-(4-pyrudyl)-1H-imidazole (SB203580) or trans-1-(4-hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxypyrimidin-4-yl)imidazole (SB239063), prevented the induction of depotentiation by LFS and CPA. In agreement with electrophysiological observation, both LFS- and CPA-induced depotentiation are associated with an increase in p38 MAPK activation, which are blocked by DPCPX or SB203580 application.

Conclusion

These results suggest that activation of adenosine A₁ receptor and in turn triggering p38 MAPK signaling may contribute to the LFS-induced depotentiation at hippocampal CA1 synapses.     

Histaminergic Activity in a Rodent Model of Parkinson’s Disease

Rats lesioned shortly after birth with 6-OHDA have been proposed to be a near-ideal model of severe Parkinson’s disease, because of non-lethality of the procedure, near-total destruction of nigrostriatal dopaminergic fibers, and near-total dopamine (DA) denervation of striatum. There are scarce data that in Parkinson’s disease, activity of the central histaminergic system is increased. Therefore, the aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats. At 3 days after birth, Wistar rats were pretreated with desipramine (20.0 mg/kg ip) 1 h before bilateral icv administration of the catecholaminergic neurotoxin 6-OHDA (67 μg base, on each side) or saline-ascorbic acid (0.1%) vehicle (control). At 8 weeks levels of DA and its metabolites l-3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) were estimated in the striatum and frontal cortex by HPCL/ED technique. In the hypothalamus, hippocampus, frontal cortex, and medulla oblongata, the level of histamine was analyzed by immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped-activity) were additionally made on control and 6-OHDA neonatally lesioned rats. Effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists (e.g., S(+)chlorpheniramine, H₁; cimetidine, H₂; thioperamide, H₃ agonist) were determined. We confirmed that 6-OHDA significantly reduced contents of DA and its metabolites in the brain in adulthood. Histamine content was significantly increased in the hypothalamus, hipocampus, and medulla oblongata. Moreover, in 6-OHDA-lesioned rats behavioral response was altered mainly by thioperamide (H₃ antagonist). These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson’s disease, and that histaminergic neurons exert a modulating role in Parkinsonian 6-OHDA-lesioned rats.     

Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate

Background

Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters.

Characteristics of the sympathetic innervation of the nictitating membrane and of the vasculature of the nose and tongue of the cat

Summary Vasomotor responses from the nasal mucosa and tongue, and contractions of the nictitating membrane, were recorded on stimulation of the cervical sympathetic or internal carotid nerves.Preganglionic sympathetic nerve fibres which elicited a membrane response possessed a lower threshold than those which evoked nasal vasoconstriction, while the latter displayed a lower threshold than fibres which evoked tongue vasoconstriction. The sympathetic vasodilator fibres to the tongue, whose activity was revealed after-receptor blockade, had a similar threshold to the vasoconstrictor fibres.Membrane contraction, nasal vasoconstriction and occasionally tongue vasoconstriction could be evoked by stimulating the internal carotid nerve. The postganglionic fibres innervating the nasal mucosa had a similar threshold to those of the nictitating membrane, which may indicate that there are small myelinated fibres innervating the mucosa.The preganglionic compound nerve action potential had four major components, S₁–S₄. S₁, S₂ and usually S₃ fibres were associated with membrane contraction; S₂, S₃ and sometimes S₁ fibres were associated with nasal vasoconstriction; and S₃, usually S₂ and occasionally S₁ fibres were associated with vasoconstriction in the tongue. It is concluded that each of these three groups of nerve fibres, but not S₄ fibres, may include fibres associated functionally with the three effectors.There was a considerable difference between the relative amplitude of the responses of the three effectors elicited by stimulation of the cervical sympathetic nerve at frequencies between 0.2 and 2 Hz. Vasoconstrictor responses were relatively larger than membrane contractions suggesting differences in the mechanisms of neurotransmission at the neuroeffector junctions.     

Beta2-adrenoceptor stimulation has no effect on skeletal muscle glucose uptake

Introduction

Blockade of the β-adrenergic receptor induces insulin resistance and chronic β-adrenoceptor stimulation improves insulin sensitivity in animals. We tested whether acute β₂-adrenoceptor stimulation increased insulin-induced glucose uptake in human forearm skeletal muscle.

Materials and Methods

During a hyperinsulinemic euglycemic clamp procedure, forearm glucose uptake was calculated by multiplying the arteriovenous glucose gradient and forearm blood flow before and during local infusion of the β₂-adrenoceptor salbutamol into the brachial artery.

Conclusions

β₂-adrenergic stimulation had no effect on insulin-stimulated glucose uptake in human forearm skeletal muscle.     

PAI-1-Derived Peptide EEIIMD Prevents Hypoxia/Ischemia-Induced Aggravation of Endothelin- and Thromboxane-Induced Cerebrovasoconstriction

Background

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery or post delivery respiratory management. The sole FDA approved treatment for acute stroke is tissue-type plasminogen activator (tPA). Endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after H/I in pigs. Mitogen-activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to impaired vasodilation. This study examined the hypothesis that H/I aggravates the vascular response to two important procontractile mediators released during CNS ischemia, endothelin-1 (ET-1) and thromboxane, which is further enhanced by tPA and ERK MAPK.

Methods

Cerebral hypoxia (pO₂ 35 mmHg for 10 min via inhalation of N₂) followed immediately by ischemia (global intracranial pressure elevation for 20 min) was produced in chloralose anesthetized piglets equipped with a closed cranial window.

Results

H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimetic U 46619. Potentiated vasoconstrictor responses were blocked by EEIIMD, an inhibitor of tPA’s signaling and vascular activities, but unchanged by its inactive analogue EEIIMR. The cerebrospinal fluid concentration of ERK MAPK determined by ELISA was increased by H/I, potentiated by tPA, but blocked by EEIIMD. The ERK MAPK antagonist U 0126 blocked H/I augmented enhancement of ET-1 and U 46619 vasoconstriction.

Conclusions

These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction by upregulating endogenous tPA and ERK MAPK.     

Neural circuits and temporal plasticity in hindlimb representation of rat primary somatosensory cortex: revisited by multi-electrode array on brain slices

Objective

The well-established planar multi-electrode array recording technique was used to investigate neural circuits and temporal plasticity in the hindlimb representation of the rat primary somatosensory cortex (S1 area).

Methods

Freshly dissociated acute brain slices of rats were subject to constant perfusion with oxygenated artificial cerebrospinal fluid (95% O₂ and 5% CO₂), and were mounted on a Med64 probe (64 electrodes, 8×8 array) for simultaneous multi-site electrophysiological recordings. Current sources and sinks across all the 64 electrodes were transformed into two-dimensional current source density images by bilinear interpolation at each point of the 64 electrodes.

Results

The local intracortical connection, which is involved in mediation of downward information flow across layers II–VI, was identified by electrical stimulation (ES) at layers II–III. The thalamocortical connection, which is mainly involved in mediation of upward information flow across layers II–IV, was also characterized by ES at layer IV. The thalamocortical afferent projections were likely to make more synaptic contacts with S1 neurons than the intracortical connections did. Moreover, the S1 area was shown to be more easily activated and more intensively innervated by the thalamocortical afferent projections than by the intracortical connections. Finally, bursting conditioning stimulus (CS) applied within layer IV of the S1 area could successfully induce long-term potentiation (LTP) in 5 of the 6 slices (83.3%), while the same CS application at layers II–III induced no LTP in any of the 6 tested slices.

Conclusion

The rat hindlimb representation of S1 area is likely to have at least 2 patterns of neural circuits on brain slices: one is the intracortical circuit (ICC) formed by interlaminar connections from layers II–III, and the other is the thalamocortical circuit (TCC) mediated by afferent connections from layer IV. Besides, ICC of the S1 area is spatially limited, with less plasticity, while TCC is spatially extensive and exhibits a better plasticity in response to somatosensory afferent stimulation. The present data provide a useful experimental model for further studying microcircuit properties in S1 cortex at the network level in vitro.     

Thyroid function in clinical subtypes of major depression: an exploratory study

Background

Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences.

Methods

We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D₄ receptor (DRD4), and the dopamine β-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90).

Results

The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites.

Conclusions

The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system.     

Synthesis,Biological Evaluation,and Computational Studies of Tri- and Tetracyclic Nitrogen-Bridgehead Compounds as Potent Dual-Acting AChE Inhibitors and hH3 Receptor Antagonists

相似文献   

Inhibition of sympathetic cholinergic vasodilatation by a selective NPY Y2 receptor agonist in the gracilis muscle of anaesthetised dogs

Neuropeptide Y (NPY) is known to be co-stored and co-released from sympathetic nerve terminals. In the cardiovascular system NPY acts on two main receptor subtypes. At the postjunctional or Y₁ receptor NPY causes constriction directly in addition to potentiating other vasoconstrictor agents. NPY acting at the prejuctional, or Y₂ receptor, inhibits the release of neurotransmitter from autonomic nerve terminals. In these experiments we used the selective Y₂ receptor agonist N-acetyl[Leu²⁸, Leu³¹]NPY24–36 to examine the role of NPY in the modulation of sympathetic vascular control in skeletal muscle in anaesthetised dogs. No systemic pressor or local constrictor activity was observed in response to N-acetyl[Leu²⁸, Leu³¹]NPY24–36 administration, therefore allowing us to examine the neuroinhibitory actions of NPY in the absence of direct vascular effects on blood flow. Stimulation of the sympathetic nerves to the gracilis muscle engages both sympathetic cholinergic and sympathetic adrenergic fibres and produces an initial vasodilatation followed by a slower vasoconstriction. Nerve evoked vasodilatation was inhibited by over 50% in the presence of the selective NPY Y₂ agonist N-acetyl[Leu²⁸, Leu³¹]NPY24–36. This dilatation was abolished by atropine, confirming its cholinergic nature. N-Acetyl[Leu²⁸, Leu³¹]NPY24–36 was found to have no effect on nerve evoked vasoconstriction. The results demonstrate a NPY Y₂-receptor mediated inhibition of nerve evoked sympathetic cholinergic vasodilatation but not of sympathetic vasoconstriction.     

Lack of association between ADRA2B -4825 gene insertion/deletion polymorphism and migraine in Chinese Han population

Objective

The present study aimed to estimate the association between susceptibility to migraine and the 12-nucleotide insertion/deletion (indel) polymorphism in promoter region of α_2B-adrenergic receptor gene (ADRA2B).

Methods

A case-control study was carried out in Chinese Han population, including 368 cases of migraine and 517 controls. Genomic DNA was extracted from blood samples, and DNA fragments containing the site of polymorphism were amplified by PCR. Data were adjusted for sex, age, migraine history and family history, and analyzed using a logistic regression model.

Results

There was no association between indel polymorphism and migraine, at either the allele or the genotype level.

Conclusion

These findings do not support a functional significance of ADRA2B indel polymorphism at position -4825 relative to the start codon in the far upstream region of the promoter in the present migraine subjects.     

Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction of long-term potentiation in rats

Objective

To explore the role of the extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) pathway in the induction of long-term potentiation (LTP) in the anterior cingulate cortex (ACC) that may be implicated in pain-related negative emotion.

Methods

LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK (pERK) and phospho-CREB (pCREB) were examined using immunohistochemistry method.

Results

LTP could be induced stably in ACC slice by high frequency stimulation (2-train, 100 Hz, 1 s), while APv (an antagonist of NMDA receptor) could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 (50 μmol/L), a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 min and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB.

Conclusion

NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.     

Somatostatin receptor subtype 2 (sst2) is a potential prognostic marker and a therapeutic target in medulloblastoma

Introduction

Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst₂). It controls proliferation of both normal and neoplastic cells. sst₂ has thus been suggested as a therapeutic target and prognostic marker for certain malignancies.

Methods

To assess global expression patterns of sst ₂ mRNA, we evaluated normal (n?=?353) and tumor tissues (n?=?340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst ₂ mRNA in medulloblastoma (p?<?0.001). sst₂ protein was investigated by immunohistochemistry in two independent cohorts.

Results

Correlation of sst₂ protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p?<?0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst₂, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst₂ expression (p?=?0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples.

Conclusion

sst₂ is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target.     

Sympathetic cardiovascular hyperactivity precedes brain death

Objective

The time preceding brain death is associated with complex dysregulation including autonomic dysfunction that may compromise organ perfusion, thus inducing final organ failure. In this study, we assessed autonomic function in patients prior to brain death.

Methods

In 5 patients (2 women, median 60 years, age range 52–75 years) with fatal cerebral hemorrhage or stroke and negative prognosis, we monitored RR-intervals (RRI), systolic and diastolic blood pressure (BP), and oxygen saturation. Adjustment of mechanical ventilation remained constant. We assessed autonomic function from spectral powers of RRI and BP in the mainly sympathetic low- (LF, 0.04–0.15 Hz) and parasympathetic high-frequencies (HF, 0.15–0.5 Hz), and calculated the RRI-LF/HF-ratio as index of sympathovagal balance. Three patients required norepinephrine (0.5–1.6 mg/h) for up to 72 h to maintain organ perfusion. Norepinephrine was reduced to 0.2–0.5 mg/h within 2 h before brain death was diagnosed according to the criteria of the German Medical Association. Wilcoxon test compared average values of ten 2-min epochs determined 2–3 h (measurement 1) and 1 h (measurement 2) before brain death.

Results

We found higher systolic (127.3 ± 15.9 vs. 159.4 ± 44.8 mmHg) and diastolic BP (60.1 ± 15.6 vs. 74.0 ± 15.2 mmHg), RRI-LF/HF-ratio (1.2 ± 1.6 vs. 3.9 ± 4.0), and BP-LF-powers (2.7 ± 4.8 vs. 23.1 ± 28.3 mmHg²) during measurement 2 than during measurement 1 (p < 0.05).

Conclusions

The increase in BPs, in sympathetically mediated BP-LF-powers, and in the RRI-LF/HF-ratio suggests prominent sympathetic activity shortly before brain death. Prefinal sympathetic hyperactivity might cause final organ failure with catecholamine-induced tissue damage which impedes post-mortem organ transplantation.     

Associations Between Socioeconomic Status and Catecholamine Levels Vary by Acculturation Status in Mexican-American Women

Background

Lower socioeconomic status (SES) is associated with poorer health, possibly through activation of the sympathetic nervous system.

Purpose

This study aimed to examine the association between SES and catecholamine levels, and variations by acculturation.

Methods

Three hundred one Mexican-American women underwent examination with a 12-h urine collection. Analyses tested associations of SES, acculturation (language and nativity), and their interaction with norepinephrine (NOREPI) and epinephrine (EPI).

Results

No main effects for SES or the acculturation indicators emerged. Fully adjusted models revealed a significant SES by language interaction for NOREPI (p?<?.01) and EPI (p?<?.05), and a SES by nativity interaction approached significance for NOREPI (p?=?.05). Simple slope analyses revealed that higher SES related to lower catecholamine levels in Spanish-speaking women, and higher NOREPI in English-speaking women. Although nonsignificant, similar patterns were observed for nativity.

Conclusions

Associations between SES and catecholamines may vary by acculturation, and cultural factors should be considered when examining SES health effects in Hispanics.     

Comparison of Non-invasive and Invasive Arterial Blood Pressure Measurement for Assessment of Dynamic Cerebral Autoregulation

Background

There is a growing interest in measuring cerebral autoregulation in patients with acute brain injury. Non-invasive finger photo-plethysmography (Finapres) is the method of choice to relate arterial blood pressure to changes in cerebral blood flow. Among acutely ill patients, however, peripheral vasoconstriction often limits the use of Finapres requiring direct intravascular blood pressure measurement. We evaluated how these two different forms of blood pressure monitoring affect the parameters of dynamic cerebral autoregulation (DCA).

Methods

We performed 37 simultaneous recordings of BP and cerebral blood flow velocity in 15 patients with acute brain injury. DCA was estimated in the frequency domain using transfer function analysis to calculate phase shift, gain, and coherence. In addition the mean velocity index (Mx) was calculated for assessment of DCA in the time domain.

Results

The mean patient age was 58.1 ± 15.9 years, 80 % (n = 12) were women. We found good inter-method agreement between Finapres and direct intravascular measurement using Bland–Altman and correlation analyses. Finapres gives higher values for the efficiency of dynamic CA compared with values derived from radial artery catheter, as indicated by biases in the phase (26.3 ± 11.6° vs. 21.7 ± 10.5°, p = 0.001) and Mx (0.571 ± 0.137 vs. 0.649 ± 0.128, p < 0.001). Gain in the low frequency range did not significantly differ between the two arterial blood pressure methods. The average coherence between CBFV and ABP was higher when BP was measured with arterial catheter for frequencies above 0.05 Hz (0.8 vs. 0.73, p < 0.001).

Conclusion

Overall, both methods yield similar results and can be used for the assessment of DCA. However, there was a small but significant difference for both mean Mx and phase shift, which would need to be adjusted for during monitoring of patients when using both methods. When available, invasive arterial blood pressure monitoring may improve accuracy and thus should be the preferred method for DCA assessment in the ICU.     

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC^-/-) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 μg/5 μL) significantly suppressed autotomy behavior in rats. HDC^-/- mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H₁ receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H₁ receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.     

Are the disparate pharmacological profiles of competitive and un-competitive NMDA antagonists due to different baseline activities of distinct glutamatergic pathways? (Hypothesis)

Summary In superfused mouse striatal slices preincubated with [³H] dopamine 25 nmol/l, the electrically (3 Hz) evoked tritium overflow was inhibited by histamine 10 mol/l by 18%. The degree of inhibition was increased to 38% by haloperidol but not affected by (1) atropine, (2) reducing the stimulation frequency to 0.3 Hz or (3) increasing the concentration of [³H]dopamine (used for preincubation) to 100 nmol/l. The effect of histamine was mimicked by the H₃ agonist R-(–)--methylhistamine; it was not affected by the H₁ antagonist dimetindene and the H₂ antagonist ranitidine but abolished by the H₃ antagonist thioperamide. Tritium overflow evoked by Ca²⁺ ions (introduced into Ca²⁺free, K⁺-rich medium containing tetrodotoxin) was not affected by histamine 10 mol/l in the absence, but inhibited (by 30%) in the presence of haloperidol; the effect of histamine was abolished by thioperamide. In conclusion, the dopaminergic nerve terminals in the mouse striatum are endowed with presynaptic H₃ receptors. Simultaneous blockade of dopamine autoreceptors increases the extent of the H₃ receptor-mediated inhibition of dopamine release.     

Autonomic mechanisms associated with heart rate and vasoconstrictor reserves

Introduction

Hemorrhage is accompanied by baroreflex-mediated tachycardia and vasoconstriction. The difference between baseline and maximum responses is defined as the heart rate (HR) and vasoconstrictor ??reserve??.

Objective

To test the hypothesis that higher HR and vasoconstrictor reserves in subjects with high tolerance (HT) to central hypovolemia is associated with greater reserve for sympathoexcitation and vagal withdrawal compared with low tolerant (LT) subjects.

Methods

R?CR intervals (RRI), systolic arterial pressure (SAP), estimated stroke volume, and muscle sympathetic nerve activity (MSNA) were measured during lower body negative pressure (LBNP) designed to induce pre-syncope. Subjects with tolerance ??60?mmHg LBNP were classified as LT (n?=?22) while subjects who tolerated LBNP levels >60?mmHg were classified as HT (n?=?56). Spontaneous cardiac baroreflex sensitivity (BRS) was assessed via RRI-SAP down?Cdown sequences.

Results

HR reserve in HT subjects (+52?±?2?bpm) was twofold greater (P?P?=?0.04) than that of the LT group (+1.9?±?0.3?pru). HT subjects demonstrated greater (P????0.03) BRS reserve (?14.2?±?1.8?ms/mmHg) and MSNA reserve (+41?±?2 bursts/min) compared with LT subjects (?7.4?±?1.7?ms/mmHg and +26?±?7?bursts/min).

Interpretation

Our data support the hypothesis that greater physiological reserve capacity for tachycardia and vasoconstriction related to high tolerance to central hypovolemia is associated with greater reserves for sympathoexcitation and cardiac vagal withdrawal.     

Therapeutic Hypothermia Reduces Middle Cerebral Artery Flow Velocity in Patients with Severe Aneurysmal Subarachnoid Hemorrhage

Background

Transcranial Doppler (TCD) is widely used to detect and follow up cerebral vasospasm after subarachnoid hemorrhage (SAH). Therapeutic hypothermia might influence blood flow velocities assessed by TCD. The aim of the study was to evaluate the effect of hypothermia on Doppler blood flow velocity after SAH.

Methods

In 20 patients treated with hypothermia (33°) due to refractory intracranial hypertension or delayed cerebral ischemia (DCI), mean flow velocity of the middle cerebral artery (MFV_MCA) was assessed by TCD. Thirteen patients were treated with combined hypothermia and barbiturate coma and seven with hypothermia alone. MFV_MCA was obtained within 24 h before and after induction of hypothermia as well as before and after rewarming.

Results

Hypothermia was induced on average 5 days after SAH (range 1–12) and maintained for 144 h (range 29–270). After hypothermia induction, MFV_MCA decreased from 113.7 ± 49.0 to 93.8 ± 44.7 cm/s (p = 0.001). The decrease was independent of SAH-related complications and barbiturate coma. MFV_MCA further decreased by 28.2 cm/s between early and late hypothermia (p < 0.001). This second decrease was observed in patients with DCI (p < 0.001), but not in patients with intracranial hypertension (p = 0.715). Compared to late hypothermia, MFV_MCA remained unchanged after rewarming (65.6 ± 32.1 vs 70.3 ± 36.8 cm/s; p = 0.219). However, patients treated with hypothermia alone showed an increase in MFV_MCA after rewarming (p = 0.016).

Conclusion

Therapeutic hypothermia after SAH decreases Doppler blood flow velocity in both intracranial hypertension and DCI cases. The results can be the effect of hypothermia-related mechanisms or resolving cerebral vasospasm during prolonged hypothermia.