piperidines and Subarachnoid-Hemorrhage

The efficacy and safety of a new platelet-activating factor receptor antagonist, E5880, were investigated for preventing cerebral vasospasm after subarachnoid hemorrhage (SAH) in 71 patients with SAH who underwent surgery for ruptured aneurysms within 3 days. Intravenous E5880 administration (300 micrograms or 1200 micrograms twice daily) was begun within 4 days and continued for 14 days. The incidence of symptomatic vasospasm, low-density area on computed tomography, and angiographic vasospasm was lower than in placebo groups in previous studies. Clinical outcome was favorable compared with previous studies. No clinically important adverse events were observed. These results suggest that E5880 is safe and effective in the treatment of patients with cerebral vasospasm due to SAH.

Topics: Adult; Aged; Aneurysm, Ruptured; Brain; Clinical Protocols; Dose-Response Relationship, Drug; Female; Humans; Incidence; Injections, Intravenous; Intracranial Aneurysm; Male; Middle Aged; Piperidines; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pyridinium Compounds; Radiography; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Endovascular perforation was performed to establish a SAH model of rats. ACEA was administered intraperitoneally 1 h after SAH. The CB1R antagonist AM251 was injected intraperitoneally 1 h before SAH induction. Adenoassociated virus- (AAV-) Nrf1 shRNA was infused into the lateral ventricle 3 weeks before SAH induction. Neurological tests, immunofluorescence, DHE, TUNEL, Nissl staining, transmission electron microscopy (TEM), and Western blot were performed.. The expression of CB1R, Nrf1, PINK1, Parkin, and LC3II increased and peaked at 24 h after SAH. ACEA treatment exhibited the antioxidative stress and antiapoptosis effects after SAH. In addition, ACEA treatment increased the expression of Nrf1, PINK1, Parkin, LC3II, and Bcl-xl but repressed the expression of Romo-1, Bax, and cleaved caspase-3. Moreover, the TEM results demonstrated that ACEA promoted the formation of mitophagosome and maintained the normal mitochondrial morphology of neurons. The protective effect of ACEA was reversed by AM251 and Nrf1 shRNA, respectively.. This study demonstrated that ACEA alleviated oxidative stress and neurological dysfunction by promoting mitophagy after SAH, at least in part via the CB1R/Nrf1/PINK1 signaling pathway.

Topics: Animals; Antioxidants; Apoptosis; Arachidonic Acids; Disease Models, Animal; Gene Knockdown Techniques; Male; Mitophagy; Neurons; Neuroprotective Agents; Nuclear Respiratory Factor 1; Oxidative Stress; Piperidines; Protein Kinases; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Signal Transduction; Subarachnoid Hemorrhage; Treatment Outcome

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca

Topics: Animals; Blood-Brain Barrier; Glutamic Acid; Humans; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Subarachnoid Hemorrhage

Oxidative stress and neuronal apoptosis are considered crucial therapeutic targets against early brain injury (EBI) after subarachnoid hemorrhage (SAH). Emerging evidence indicates that mitochondrial dysfunction is the main reason for oxidative stress and neuronal apoptosis. MitoNEET, an outer mitochondrial membrane protein, has been shown to regulate mitochondrial function. However, whether mitoNEET activation attenuates oxidative stress and neuronal apoptosis after SAH remains unknown. This study was therefore conducted to verify the neuroprotective role of mitoNEET in EBI after SAH in rats. A total of 93 rats were subjected to an endovascular perforation model of SAH. TT01001, a selective agonist of mitoNEET, was administered intraperitoneally 1 h after SAH induction. Neurological tests, immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining, dihydroergotamine (DHE) staining, and western blot experiments were performed. The results showed that MitoNEET is expressed in neurons, but significantly decreased at 24 h after SAH induction. Activating mitoNEET with TT01001 significantly improved the neurological deficits, and reduced oxidative stress and neuronal apoptosis as measured by DHE and TUNEL staining, when compared with the SAH+vehicle group. Furthermore, TT01001 treatment decreased the expression of the proapoptotic marker, Bax, while increasing the expression of the antiapoptotic marker, Bcl-2. Together, our results suggested that mitoNEET activation with TT01001 reduced oxidative stress injury and neuronal apoptosis by improving mitochondrial dysfunction in EBI after SAH.

Topics: Animals; Apoptosis; Male; Mitochondria; Mitochondrial Proteins; Neurons; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Piperidines; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Thiourea

The integrity of the blood-brain barrier (BBB) plays a vital role in affecting the prognosis of subarachnoid hemorrhage (SAH). This study aimed to investigate activation of the Tropomyosin-related kinase receptor B (TrkB) and its downstream signaling pathway on preserving BBB breakdown after experimental SAH. An endovascular perforation SAH model was applied. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2- oxopiperidine-3-carboxamide (HIOC), the derivative of N-acetyl serotonin (NAS), was intracerebroventricularly administered 3 h after SAH induction. The neurologic scores and brain water content were evaluated in an outcome study. Western blot and immunofluorescence staining were used to investigate the mechanism. The results indicated that HIOC activated the TrkB/Akt pathway, increased the tight junction expression, improved neurologic deficits, and ameliorated brain edema after SAH. Thus, we conclude that initiating the TrkB/Akt signaling cascade preserves BBB breakdown after experimental SAH in rats.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Glycogen Synthase Kinase 3 beta; Indoles; Male; Piperidines; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptor, trkB; Signal Transduction; Subarachnoid Hemorrhage; Water

Under physiologic conditions, losartan showed a dose-dependent antagonistic effect to the endothelin-1 (ET-1)-mediated vasoconstriction. This reduced vasoconstriction was abolished after preincubation with an endothelin B

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensins; Animals; Basilar Artery; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Losartan; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation; Vasospasm, Intracranial

Delayed cerebral vasospasm is a main cause of morbidity and mortality as well as poor outcome in patients following aneurysmal subarachnoid hemorrhage (SAH). In this study, the effect of the bronchodilator KMUP-3 (7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) on basilar artery narrowing, neurological outcome, and expression of rhoA/rho kinase II (ROCKII), rhoA, and protein kinase C (PKC) γ proteins were evaluated in a rat model of SAH. SAH was induced by double injection of autologous blood into the cistern magna on days 0 and 3. KMUP-3 was administered (0.3 mg/kg/day) by osmotic minipumps implanted subcutaneously (beginning day -3 in pretreatment group and at 1 h after the initiation of the first autologous blood injection in the treatment group). Neurological outcome was assessed by ambulation and placing/stepping reflex responses at 48 h after the second injection of autologous blood. Tissue morphology and protein expression were conducted on day 7 post-day 0 injection. Both KMUP-3 treatment regimens significantly improved neurological outcome and completely attenuated basilar artery narrowing as well as reduced the enhancement of ROCKII, rhoA, and PKCγ protein expression in rats subjected to SAH, compared with normal and untreated SAH rats. These results suggest that KMUP-3 may be a novel agent for the treatment of cerebral vasospasm following SAH.

Topics: Animals; Bronchodilator Agents; Disease Models, Animal; Drug Interactions; Gene Expression Regulation; Hemodynamics; Locomotion; Male; Neurologic Examination; Piperidines; Protein Kinase C; Rats; Rats, Sprague-Dawley; Reflex; rho-Associated Kinases; rhoA GTP-Binding Protein; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Xanthines

Approximately 50% of patients who survived after aneurysmal subarachnoid hemorrhage (SAH) have cognitive or neurobehavioral dysfunction. The mechanisms are not known. NR2B, one of the subunits of N-methyl-d-aspartate (NMDA) receptors, has been proved to be an important factor for synapse function and behavior cognition. Experiment 1 aimed to investigate the timecourse of the NR2B expression in the cortex, hippocampus, and cerebellum after SAH in rats. In experiment 2, we assessed the effect of Ro 25-6981 (a specific NR2B antagonist) on regulation of learning deficits and behavioral activity following SAH. All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once on day 0. NR2B was assessed by Western blot analysis and immunohistochemistry. Cognitive and memory changes were investigated in the Morris water maze. As a result, the expression of NR2B was decreased remarkably in SAH groups compared with the control group and the low ebb was on days 1-3. The immunohistochemical staining demonstrated expression of NR2B was present mainly in the neurons in all of the three different regions, such as the cortex, hippocampus, and cerebellum. After Ro 25-6981 intraperitoneal administration, learning deficits induced by SAH was markedly aggravated and clinical behavior scale was also significantly decreased. Our results suggest that NR2B expression is down-regulated in the brain after experimental SAH and NR2B antagonism resulted in augmentation of the development of cognitive dysfunction after SAH.

Topics: Animals; Behavior, Animal; Cerebellum; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Down-Regulation; Hippocampus; Maze Learning; Neurons; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Subarachnoid Hemorrhage

Alterations in the activity of vascular K channels are commonly associated with abnormalities in cerebral vascular function after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage-induced vasospasm remains incompletely understood; nevertheless, activation of K channels may be of benefit in relieving spastic constriction. This study was to examine whether the vasodilators KMUP-1 and pinacidil, a KATP-channel opener, have the ability to prevent SAH-induced vasospasm via the large-conductance Ca-activated K (BKCa) channels in cerebral arteries. Rats were divided into four groups including sham-operated, SAH, KMUP-1 treated, and pinacidil treated. Subarachnoid hemorrhage rats were induced by injecting autologous blood into cisterna magna, and then KMUP-1 or pinacidil (1 mg/kg) was injected intraperitoneally 1 and 24 h after SAH. Behavioral tests were assessed on day 2 after SAH before the rats were killed. Cerebral myocytes were enzymatically isolated from rat basilar arteries and used to monitor BKCa-channel activities. In isolated basilar arteries, KMUP-1-treated and pinacidil-treated rats showed normalized vascular reactivity. In whole-cell recordings, BKCa currents were attenuated in SAH rats compared with sham-operated rats. In inside-out patches, the conductance and voltage sensitivity of single BKCa-channels were unchanged among the four groups. In contrast, SAH rats showed markedly decreased BKCa-channel activity and β1-subunit expression associated Ca sensitivity that was further confirmed by immunofluorescence staining and Western blotting. Subarachnoid hemorrhage-induced deficits in motor function and BKCa-channel inhibition were improved by KMUP-1-treated and pinacidil-treated rats. In addition, SAH appears to modify BKCa-channel calcium sensitivity. KMUP-1 and pinacidil prevent SAH-induced vasospasm at least in part by the restoration of BKCa-channel activities.

Topics: Animals; Basilar Artery; Down-Regulation; Large-Conductance Calcium-Activated Potassium Channels; Male; Muscle, Smooth, Vascular; Pinacidil; Piperidines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilator Agents; Vasospasm, Intracranial; Xanthines

A 70-year-old woman underwent emergent clipping surgery for subarachnoid hemorrhage under general anesthesia. Her laboratory data showed thrombocytopenia (4.0 x 10(4) microl(-1)). She had taken prednisolone (3 mg x day(-1)) and methotrexate (MTX) (10 mg x week(-1)) for rheumatoid arthritis for the last 10 years. Anesthesia was induced with remifentanil as well as propofol, maintained with remifentanil and sevoflurane in oxygen. The operation was performed uneventfully without platelet transfusion. Since the cause of thrombocytopenia was suspected to be MTX, we started rescue therapy by calcium folinate postoperatively. Platelet count was normalized two days later (11.6 x 10(4) microl(-1)). One month after the operation, she was discharged uneventfully.

Topics: Aged; Anesthesia, General; Arthritis, Rheumatoid; Emergencies; Female; Humans; Immunosuppressive Agents; Intracranial Aneurysm; Leucovorin; Methotrexate; Piperidines; Platelet Transfusion; Postoperative Care; Propofol; Remifentanil; Subarachnoid Hemorrhage; Thrombocytopenia; Treatment Outcome; Vascular Surgical Procedures

Topics: Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Local; Antiemetics; Carotid Artery, Internal; Dexamethasone; Granisetron; Humans; Intracranial Aneurysm; Intubation, Intratracheal; Lidocaine; Male; Middle Aged; Piperidines; Postoperative Complications; Remifentanil; Subarachnoid Hemorrhage; Surgical Mesh; Time Factors

The 53-year-old female patient had suffered massive subarachnoid bleeding due to rupture of left-localized aneurysm of the anterior communicant artery. Following the neurosurgical intervention, deterioration of consciousness related to strong vasospasm occurred. Cerebral CT examination was performed, showing a 0.5 cm ischaemic lesion of the left hippocampal fornix. Due to intensive therapy, the patient recovered gradually, however considerable short-time memory deficit and severe anterograde amnesia remained. Admission of the patient in psychiatric care 5 weeks after the operation was necessary since acute deterioration had been added to memory disturbance and anterograde amnesia. Clinical features included severe short-time memory deficit, continuous and severe anterograde amnesia, disorientation, alterations of verbal fluency and abstraction. The amnesic syndrome was probably related to the hippocampal damage, but considering the development of cognitive deficits, cerebral CT was performed again, which verified internal hydrocephalus. A ventriculo-peritoneal shunt has been implanted and the patient was re-admitted in psychiatry care because of her memory deficit, anterograde amnesia and disorientation. Thereafter, low doses of citalopram and donepezil therapy was started together with temporarily used antipsychotic medication (risperidone). Gradual, but continuous improvement of memory and cognitive function could be detected, with total recovery after one year. The deficits in long- and short-term memory, orientation and cognition were totally restored.

Topics: Amnesia, Anterograde; Citalopram; Donepezil; Female; Fornix, Brain; Humans; Indans; Intracranial Aneurysm; Korsakoff Syndrome; Middle Aged; Neurosurgical Procedures; Nootropic Agents; Piperidines; Risperidone; Rupture, Spontaneous; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Topics: Adult; Anesthesia, Conduction; Anesthesia, General; Anesthesia, Obstetrical; Brain Edema; Cesarean Section; Contraindications; Emergencies; Female; Hemodynamics; Humans; Infant, Newborn; Intracranial Arteriovenous Malformations; Male; Piperidines; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Trimester, Third; Remifentanil; Respiratory Distress Syndrome, Newborn; Subarachnoid Hemorrhage; Vasospasm, Intracranial; Vertebral Artery

We investigated the effects of a platelet-activating factor (PAF) antagonist, E5880 (1-ethyl-2-[N-(2-methoxy)benzoyl-N-[(2)-2-methoxy-3-(4-octadecycarbamoylox)piperidinocarbonyloxy-propyloxy]carbonyl]aminomethyl-pyridiniumchloride), on subarachnoid hemorrhage-induced prolongation of cerebral circulation time and decrease in the basilar artery diameter in a canine double-hemorrhage model. Animals were assigned to three groups, control (saline), E5880 1.2 mg/kg and E5880 2.4 mg/kg. For measurement of cerebral circulation time, regions of interest were chosen at the basilar artery and the straight sinus in order to obtain time-density curves. Cerebral circulation time was defined as the difference between the arterial and venous peaks. Cerebral circulation time and basilar artery diameter were assessed by intra-arterial digital subtraction angiography (IA-DSA) on Days 0, 2 and 7. The prolongation of cerebral circulation time following subarachnoid hemorrhage was significantly inhibited by intravenous administration of 2.4 mg/kg of E5880. Basilar artery constriction was also reduced by E5880. Thus, E5880 had preventive effects on the prolongation of cerebral circulation time and the vasoconstriction of basilar artery in this model. These results suggest that E5880 may have a preventive effect on neurological symptoms aggravated by cerebrovascular lesions following subarachnoid hemorrhage.

Topics: Animals; Basilar Artery; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Female; Male; Piperidines; Platelet Activating Factor; Pyridinium Compounds; Subarachnoid Hemorrhage; Time Factors; Vasoconstriction; Vasospasm, Intracranial

Remifentanil is a synthetic opiate with evident advantages for various anesthetic techniques, enhancing quality of anesthesia. Indications are increasingly well-defined. Remifentanil may be used in obstetric analgesia-anesthesia thanks to advantages demonstrated in patients with heart disease (cardiac and non-cardiac anesthesia) and in those requiring neuroanesthesia. Remifentanil is known to cross the placenta rapidly and to be rapidly metabolized and redistributed to both mother and fetus. Based on this, and on pharmacokinetic and pharmacodynamic studies in children, we judged remifentanil to be indicated for use in two patients undergoing emergency cesarean section, for whom hemodynamic stability and immediate postoperative assessment were basic requirements. The first case involved a woman 40 weeks pregnant with a history of mitral valve prolapse and an episode of acute pulmonary edema in the 28th week, who presented with ruptured membrane and the fetus in sacroposterior breech presentation without subsequent progression of labor. The second involved a woman 40-weeks pregnant with a diagnosis of Hunt-Hess grade II subarachnoid hemorrhage who had gone into labor. Outcome was satisfactory in both cases, with no complications potentially affecting the status of either mother or child. No infant respiratory insufficiency occurred and Apgar scores were favorable. We consider remifentanil to be safe and effective for general anesthesia for emergency cesarean delivery in patients with cardiac and/or neurological risk factors.

Topics: Adult; Anesthesia, General; Anesthesia, Obstetrical; Anesthetics, General; Apgar Score; Cesarean Section; Emergencies; Female; Humans; Infant, Newborn; Intracranial Aneurysm; Maternal-Fetal Exchange; Mitral Valve Prolapse; Obstetric Labor Complications; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Outcome; Pulmonary Edema; Remifentanil; Subarachnoid Hemorrhage

While it has been widely reported that the vasospasm following subarachnoid hemorrhage (SAH) is prevented/reversed by endothelin (ET) receptor antagonists selective for the ET(A) receptor and by nonselective ET receptor antagonists, ie, antagonists of both the ET(A) and ET(B) receptors, there are no reports on the possible attenuation of the spasm by selective ET(B) receptor antagonists. The purpose of this study was to investigate whether (1) ET(B) receptor antagonists prevent and reverse SAH-induced spasm and (2) attenuation of the spasm results from blockade of smooth muscle ET(B) (ET(B2)) receptor-mediated constriction and/or endothelial ET(B) (ET(B1)) receptor-mediated ET-1-induced ET-1 release.. SAH-induced spasm of the rabbit basilar artery was induced with the use of a double hemorrhage model. In vivo effects of agents on the spasm were determined by angiography after their intracisternal infusion (10 microL/h) by mini osmotic pump. In situ effects of agents on the spasm were determined by direct measurement of vessel diameter after their suffusion in a cranial window.. SAH constricted the basilar artery by 30%. Intracisternal infusion with 10 micromol/L BQ788, an ET(B1/B2) receptor antagonist, reduced the spasm to 10%. To investigate whether BQ788 prevented the spasm by blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release, as opposed to ET(B2) receptor-mediated constriction, we tested whether ET(B1) receptor blockade also prevented the spasm. Indeed, intracisternal infusion with 10 micromol/L RES-701-1, a selective ET(B1) receptor antagonist, reduced the spasm to 10%. Similarly, in situ superfusion with 1 micromol/L BQ788 reversed the spasm by 40%, and 1 micromol/L RES-701-1 reversed the spasm by 50%. However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1-induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor.. These results demonstrate that ET(B) receptor antagonists prevent and reverse SAH-induced cerebral vasospasm in an animal model. The likely mechanism underlying the attenuation of the spasm is blockade of ET(B1) receptor-mediated ET-1-induced ET-1 release of newly synthesized ET-1. These studies provide rationale for the therapeutic use of ET(B1) receptor antagonists to relieve the vasospasm following SAH, as well as other pathophysiological conditions involving possible ET-1-induced ET-1 release.

Topics: Animals; Basilar Artery; Endothelin Receptor Antagonists; Endothelin-1; Injections, Intraventricular; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Rabbits; Receptor, Endothelin B; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation

Recently, an important role of platelet-activating factor (PAF), an inflammation mediator, has been demonstrated in the genesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). In the current study, the authors examined whether intravenous administration of the novel PAF antagonist, E5880, can prevent vasospasm following SAH in rabbits. A vasospasm model was produced in three groups of rabbits using two subarachnoid injections of autologous arterial blood, followed by intravenous administration of distilled water (control), a low dose of E5880 (0.1 mg/kg in distilled water), or a high dose of E5880 (0.5 mg/kg in distilled water). Neurological deterioration was largely prevented in the rabbits that received E5880. Basilar artery constriction was also reduced by both doses of E5880. Histological examination at autopsy predominantly showed ischemic changes in the brain. Animals in each E5880-treated group exhibited ischemic changes less frequently than those in the control group. Plasma thromboxane B2 concentrations were reduced in rabbits treated with E5880. Platelet-activating factor was immunolocalized in the intima and media of the basilar artery in the control group. The PAF immunoreactivity demonstrated in the basilar artery was decreased in the E5880 groups in a dose-dependent manner. Thus, this study provides evidence that PAF may play a role in the pathogenesis of vasospasm after SAH and that intravenous administration of E5880 is a promising approach in preventing vasospasm.

Topics: Animals; Female; Ischemic Attack, Transient; Piperidines; Pyridinium Compounds; Rabbits; Subarachnoid Hemorrhage; Thromboxane B2

Serotonin released from platelets has been suggested as one substance causing the vasospasm following subarachnoid hemorrhage. We studied whether such serotonin is able to constrict pial vessels.. We studied the uptake of serotonin in pial perivascular nerves by immunohistochemistry. We measured the contractile response in rat basilar artery after in vitro incubation with serotonin and during electrical field stimulation of perivascular nerves following experimental subarachnoid hemorrhage.. After incubation with serotonin, electrical field stimulation caused a tetrodotoxin- and ketanserin-blockable contractile response. We observed no such response in vessels from rats treated with 6-hydroxydopamine or after blockade of serotonin uptake. After subarachnoid hemorrhage, a pronounced network of serotonin-immunoreactive nerve fibers was demonstrated in the vessel wall. In vessels from control rats, no serotonin fibers were seen, and in vessels from 6-hydroxydopamine-treated animals with subarachnoid hemorrhage only a few such fibers were seen. Electrical field stimulation of the basilar artery from rats tested 2 or 16 hours (but not 10 minutes or 24 hours) after subarachnoid hemorrhage showed contractile responses that were prevented by tetrodotoxin, ketanserin, and prior 6-hydroxydopamine treatment.. Our study demonstrates a capacity of the perivascular sympathetic nerves to take up serotonin both in vitro and during the early phase of subarachnoid hemorrhage. Such uptake may help to remove excess serotonin from the subarachnoid space. Only if serotonin is subsequently released upon nerve activation may minor smooth muscle contraction develop.

Topics: Animals; Basilar Artery; Electric Stimulation; Ischemic Attack, Transient; Ketanserin; Male; Oxidopamine; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Serotonin; Subarachnoid Hemorrhage; Sympathetic Nervous System; Tetrodotoxin; Vasoconstriction

Peri-aneurysmal CSF was obtained at operation from 13 patients with subarachnoid haemorrhage from ruptured intracranial aneurysms. The 5-hydroxytryptamine antagonist ketanserin inhibited contractions of isolated human intracranial arteries, elicited by this CSF. The presence of 5-HT in CSF was confirmed by high performance liquid chromatography. The use of ketanserin in the therapy of postoperative cerebral vasospasm is discussed.

Topics: Adult; Aged; Animals; Female; Humans; Hydroxyindoleacetic Acid; Intracranial Aneurysm; Intraoperative Complications; Ischemic Attack, Transient; Ketanserin; Male; Middle Aged; Piperidines; Postoperative Complications; Rats; Rupture, Spontaneous; Serotonin; Serotonin Antagonists; Subarachnoid Hemorrhage; Vasoconstriction