Iptakalim Preferentially Decreases Nicotine-induced Hyperlocomotion in Phencyclidine-sensitized Rats: A Potential Dual Action against Nicotine Addiction and Psychosis

OBJECTIVE: Iptakalim is a putative ATP-sensitive potassium (KATP) channel opener. It is also a novel nicotinic acetylcholine receptor (nAChR) blocker and can antagonize nicotine-induced increase in dopamine release in the nucleus accumbens. Our recent work also shows that iptakalim exhibits a clozapine-like atypical antipsychotic profile, indicating that iptakalim may possess a dual action against nicotine addiction and schizophrenia. METHODS: The present study examined the potential therapeutic effects of iptakalim on nicotine use in schizophrenia. We created an animal model of comorbidity of nicotine addiction and schizophrenia by injecting male Sprague-Dawley rats with nicotine (0.40 mg/kg, subcutaneously[sc]) or saline, in combination with phencyclidine (PCP, 3.0 mg/kg, sc) or saline daily for 14 consecutive days. RESULTS: During the PCP/nicotine sensitization phase, PCP and nicotine independently increased motor activity over time. PCP also disrupted prepulse inhibition (PPI) of acoustic startle response. Acute nicotine treatment attenuated the PCP-induced hyperlocomotion and PCP-induced disruption of PPI, whereas repeated nicotine treatment potentiated these effects. Importantly, pretreatment with iptakalim (10-20 mg/kg, intraperitoneally) reduced nicotine-induced hyperlocomotion in a dose-dependent fashion. This reduction effect was highly selective: it was more effective in rats previously sensitized to the combination of PCP and nicotine, but less effective in rats sensitized to saline, nicotine alone or PCP alone. CONCLUSION: To the extent that the combined nicotine and PCP sensitization mimics comorbid nicotine addiction in schizophrenia, the preferential inhibitory effect of iptakalim on nicotine-induced hyperlocomotion suggests that iptakalim may be a potential useful drug for the treatment nicotine abuse in schizophrenia.

Effects of the Antioxidant Sulforaphane on Hyperlocomotion and Prepulse Inhibition Deficits in Mice after Phencyclidine Administration

OBJECTIVE: Accumulating evidence suggests that oxidative stress plays a role in the pathophysiology of schizophrenia and that the potent antioxidants may be potential therapeutic drugs for schizophrenia. This study was undertaken to examine the effects of the potent antioxidant sulforaphane (SFN), found in cruciferous vegetables, on behavioral abnormalities (e.g., hyperlocomotion and prepulse inhibition [PPI] deficits) in mice after a single administration of the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP). METHODS: Effects of SFN (3, 10, and 30 mg/kg, intraperitoneally [i.p.]) on hyperlocomotion and PPI deficits in the adult male ddY mice after administration of PCP (3.0 mg/kg, subcutaneously [s.c.]) were examined. RESULTS: Administration of SFN (30 mg/kg, intraperitoneally [i.p.]), but not low doses (3 and 10 mg/kg, i.p.), significantly attenuated hyperlocomotion in mice after PCP administration (3.0 mg/kg, subcutaneously [s.c.]). Furthermore, administration of SFN (3, 10, and 30 mg/kg, i.p.) attenuated the PPI deficits in mice after PCP administration (3.0 mg/kg, s.c.) in a dose-dependent manner. CONCLUSION: These results suggest that SFN has antipsychotic activity in an animal model of schizophrenia. Therefore, it is likely that SFN may be a potential therapeutic drug for schizophrenia.

Modificaciones en la presión arterial y el pulso por ketamina, con y sin succinilcolina / Changes in blood pressure and heart rate by ketamine with and without succinylcholine

Introducción: La ketamina es utilizada como anestésico general, de inducción y como analgésico. Objetivos: Evaluar los cambios en la presión arterial sistólica (PAS), diastólica (PAD) y frecuencia del pulso (FP) producidos por la ketamina, y la influencia de la succinilcolina. Diseño: Comparativo y de observación. Institución: Clínica Maison de Santé, Lima, Perú. Participantes: Pacientes que recibieron ketamina. Intervenciones: La ketamina fue empleada como anestésico general único y de inducción. Por cada modalidad, se consideró doce pacientes. Los doce primeros recibieron ketamina 2 mg/kg endovenosa, con medición de la PAS, PAD y FP antes y después de la anestesia. Los otros doce recibieron ketamina más succinilcolina, midiéndose los parámetros antes y después. Se comparó los cambios. Principales medidas de resultados: Variaciones en la PAS, PAD y FP. Resultados: En los primeros doce pacientes, la ketamina elevó la PAS 26 ± 3 mmHg, p < 0,001, la PAD 19 ± 3 mmHg, p < 0,001, y la FP 15 ± 3 por minuto, p < 0,001. En los otros doce, la ketamina más succinilcolina elevaron la PAS 28 ± 3 mmHg, p < 0,001, la PAD 18 ± 2 mmHg, p < 0,001 y la FP 13 ± 1 por minuto, p < 0,001. Comparándolos porcentualmente, la succinilcolina no afectó esos cambios. Conclusiones: El incremento de la presión arterial y pulso producidos por la ketamina no fueron afectados por la succinilcolina.

Introduction: Ketamine is used as a general anesthetic as well as for anesthesia induction and analgesia. Objectives: To assess modifications in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) caused by ketamine, and if there is any influence of succinylcholine. Design: Comparative and observational study. Setting: Maison de Santé Clinic, Lima, Peru. Participants: Patients receiving ketamine. Interventions: Ketamine was used as a single drug for general anesthesia and for induction. Twelve patients were considered for each modality. The twelve first patients received ketamine, 2 mg/kg IV, and SBP, DBP and HR were measured before and after administering the drug. The second group received ketamine plus succinylcholine, and same parameters were measured. Main outcome measures: SBP, DBP, and HR variations. Results: Following ketamine injection in the first twelve patients there were elevations in SBP 26 ± 3 mmHg, p < 0,001, DBP 19 ± 3 mmHg, p < 0,001, and HR 15 ± 3 per minute, p < 0,001. In the second group after ketamine plus succinylcholine administration there were increases in SBP 28 ± 3 mmHg, p < 0,001, DBP 18 ± 2 mmHg, p < 0,001, and HR 13 ± 1 per minute, p < 0,001. There were no statistically significant differences when comparing both groups, i.e. succinlycholine did not have any influence in modifying the aforementioned parameters. Conclusions: Increases in blood pressure and heart rate induced by ketamine were not affected by succinylcholine.

Analysis of death cases involved in TASER in the State of Maryland / 法医学杂志

OBJECTIVE@#To evaluate the features of autopsy cases involved in electronic weapon (TASER) in the State of Maryland, and to discuss the appraisable points.@*METHODS@#Thirteen autopsy cases involving TASER were collected from 2004 to 2011 in the Office of the Chief Medical Examiner, State of Maryland. All the cases include detailed scene investigations, complete autopsy, toxicological analysis and histopathological examination. Statistical analysis were conducted including general information of victim, type of TASER, type of contact, toxicological results, manner and cause of death.@*RESULTS@#Majority of victims were male with an acute onset of agitated and delusional behavior. Drugs were often involved. Deaths were attributed to multiple factors.@*CONCLUSION@#Most of cases involved in TASER resulted from multiple fatal factors. Further researches are needed for the principal mechanism. Thorough scene investigation and complete autopsy examination play crucial role in evaluation of such cases.

Rapid Changes in D1 and D2 Dopamine Receptor Binding in Striatal Subregions after a Single Dose of Phencyclidine

OBJECTIVE: In humans, a single exposure to phencyclidine (PCP) can induce a schizophrenia-like psychosis which can persist for up to two weeks. In rats, an acute dose of PCP increases dopaminergic activity and causes changes in dopamine related behaviours some of which are sexually dimorphic. To better understand the effects of PCP on dopamine receptor adaptations in the short term we examined dopamine D1-like receptors (D1R) and D2-like receptors (D2R) in the mesolimbic and nigrostriatal dopamine pathways, 4 hours after exposure to PCP in female rats. METHODS: Animals received a single dose of 40 mg/kg PCP and were sacrificed 4 hours later. In vitro autoradiography was carried out using [3H] SCH 23390 and [3H] raclopride that target D1R and D2R respectively, in cryostat brain sections. RESULTS: Two way analysis of variance (ANOVA), revealed an overall effect of PCP treatment (F [1,63]=9.065; p=0.004) on D1R binding with an 18% decrease (p<0.01) in binding in the medial caudate putamen. PCP treatment also had an overall effect on D2R binding (F [1,47]=5.450; p=0.024) and a trend for an increase in D2R binding across all the brain regions examined. CONCLUSION: These results suggest opposing D1R and D2R adaptations in striatal subregions of female rats following acute exposure to PCP that may occur through indirect mechanisms.

effect of phencyclidine new derivatives on anxiety behaviors in rats

Anxiety is a common disorder which afflicts many people in any society and is often accompanied by physiological sensations such as tachycardia, chest pain, shortness of breath, insensitivity, etc. The purpose of present study was to evaluate the putative anxiolytic-like effects of phencyclidine [l-[l-phenylcyclohexyl] piperidine, CAS 956-90-1, PCP, I] and its methyl and methoxy hydroxyl derivatives [II, III] using elevated plus maze test of anxiety. Phencyclidine as well as its methyl and methoxy hydroxyl derivatives [I, II, III] [hydrochloride, 1, 2, 5 mg/kg] were synthesized and administrated intraperitoneally [IP] on adult male Wistar rats. The results of this study demonstrated that, intraperitoneal [IP] administration of PCP analogues [I, II, III] hydrochloride [1, 2, 5 mg/kg] increases the percentage of open arm time [OAT%] and percentage of open arm entries [OAE%]. This study revealed that both derivatives of phencyclidine [II, III] were more effective than PCP [I] itself in modulation of anxiety behavior in rats

Receptor antagonist of NMDA and animal models of schizophrenia / 法医学杂志

Schizophrenia is one of the common mental diseases. Because the mechanism of the schizophrenia is significantly complicated, the cause is still unknown. N-methyl-D-aspartate receptor antagonist can simulate the positive and negative symptoms, as well as the cognitive disorder of schizophrenia. Thus it has been widely used to establish the animal models of schizophrenia. The relationship of the three blocking agents of ion channels (phencyclidine, MK-801, ketamine) and the establishment of schizophrenia animal models is reviewed in this article.

Effects of a New Antipsychotic Drug (YKP1447) on Impaired Prepulse Inhibition Induced by Apomorphine and Phencyclidine in Rats / 대한정신약물학회지

OBJECTIVE: Schizophrenia, a devastating mental disorder, displays a wide range of cognitive impairments including attentional impairment. Prepulse inhibition (PPI), in which a startle response to a loud acoustic noise is reduced by a preceding auditory stimulus of a lower intensity, is impaired in schizophrenic patients and rats injected with apomorphine (APO) or phencyclidine (PCP) mimicking attentional deficits in schizophrenics. Here we examined therapeutic efficacy of a newly developed atypical antipsychotic compound (YKP1447;YKP) on PPI impairment induced by various doses of APO and PCP. METHODS: This study was composed of 3 experiments. YKP (0.5-15 mg/kg) or vehicle (VEH) was administered 15 min before the injection of APO (0.5 mg/kg, Exp1) or PCP (2.0 mg/kg, Exp2:1.5 mg/kg, Exp3). They were then tested for PPI in which a mix of startle stimulus and prepulse was presented. RESULTS: APO or PCP treatment effectively impaired PPI in tested animals (VEH/APO or VEH/PCP). Impaired PPI in APO group was reversed in animals that were pretreated with YKP (5-10 mg/kg) (Exp1). However YKP treatment was not effective in PCP group (Exp2-3). CONCLUSION: High concentration of YKP pretreatment had antipsychotic effect on APO-induced impairment in attentional function suggesting that the compound could potentially be used to treat cognitive impairment due to increased dopaminergic receptorbinding.

Modelos fisiopatológicos de la esquizofrenia; de dopamina a glutamato, de glutamato a GABA / Pathophysiologycal models of schizophrenia; from dopamine to glutamate, and glutamate to GABA

A pesar de los avances en el conocimiento de las bases biológicas de la conducta, los mecanismos neurobiológicos precisos involucrados en la esquizofrenia permanecen desconocidos. Como consecuencia de esto las terapias farmacológicas actuales descansan más sobre bases empíricas que sobre explicaciones fisiopatológicas. En el presente trabajo se propone un modelo de la esquizofrenia que podría ser de utilidad en el diseño de nuevas estrategias terapéuticas. Este modelo intenta integrar recientes hallazgos neuropsicológicos y de neuroimagen con lo que hoy sabemos respecto a la biología del desarrollo y plasticidad cerebral normal. Se propone que la esquizofrenia es una enfermedad del neurodesarrollo caracterizada por una neurotransmisión glutamatérgica inadecuadamente modulada a consecuencia de la disfunción de interneuronas GABAérgicas en múltiples regiones del cerebro. Anormalidades sutiles en el balance entre GABA y Glutamato explicarían los defectos en la cognición, la conducta social y la coordinación motora reportados en las etapas pre-psicóticas de la esquizofrenia. Más tarde en la historia natural de la enfermedad, estados hiperglutamatérgicos desencadenados por la incrementada neurotransmisión dopaminérgica propia de la peri-adolescencia y adultez temprana llevarían a la psicosis. Esta excesiva actividad glutamatérgica conduciría a su vez a las reducciones progresivas en sustancia gris y blanca observadas en recientes estudios prospectivos. En apoyo a esta hipótesis, se describen estudios propios y de otros laboratorios con pacientes esquizofrénicos, así como en un modelo animal de exposición intermitente a fenciclidina. Como corolario, drogas moduladoras de la neurotransmisión glutamatérgica, tales como acamprosato y lamotrigina, son propuestas como estrategias terapéuticas potencialmente utilizables en las etapas tempranas de la esquizofrenia.

Rol de la ketamina en la anestesia intravenosa total / Role of ketamine in total intravenous anesthesia

La disponibilidad de agentes intravenosos sedativos, hipnóticos, opioides y relajantes musculares de corta duración de acción ha promovido el avance de técnicas de anestesia intravenosa total (TIVA). La TIVA provee una inducción suave, con mínima tos o hipo, con rápido control de la profundidad anestésica y rápida emergencia con poca resaca. Es la mejor opción para pacientes de cirugía laringotraqueal, endoscopía de vías aéreas, anestesia en lugares remotos, pacientes susceptibles de hipertermia maligna o injuria radiactiva o química. La ketamina, un derivado de la fenciclidina, es el único anestésico i.v. con propiedades hipnóticas, analgésicas y amnésicas. Produce una rápida hipnosis con profunda analgesia y amnesia luego de la administración intravenosa de 0,5 a 2 mg/kg o la administración i.m. de 4-6 mg/kg (gran constante keO y rápido equilibrio entre el compartimiento donde ejerce su acción y el plasma). Niveles plasmáticos de 0,2 a 2u/ml de plasma se asocian con anestesia general. Es metabolizada en el hígado a norketamina (30 por ciento de la actividad de la droga madre) y a hidroxinorketamina, y excretada por el riñón. Interactúa con el receptor N metil D aspartato produciendo un antagonismo no competitivo e inhibiendo la actividad del glutamato y del aspartato, bloqueando la producción de óxido nítrico e inhibiendo la liberación intracelular de GMPc. Por otro lado, interactúa con el receptor opioide sigma, produciendo reacciones disfóricas. Interactúa con receptores muscarínicos M, produciendo acciones sobre la memoria, la conciencia, amnesia, dando incremento del tono simpático, broncodilatación y midriasis. La ketamina aumenta la presión intracraneal y la presión intraocular, y está contraindicada en pacientes con aumento de la presión intracraneana (trauma cerebral, masa intracraneal o hemorragia) y en trauma ocular abierto. La ketamina produce estimulación cardiovascular, con aumento de la frecuencia cardíaca, de la presión arterial y del índice cardíaco por liberación de noradrenalina, pero tiene un efecto negativo sobre la contractilidad miocárdica. La ketamina deprime la respiración a dosis mayores de 2 mg/kg o con el uso concomitante de otros depresores...

Atividade antiarritmogênica da levomepromazina em cäes submetidos à anestesia pela quetamina / The use of levomepromazine to blockade the arrhythmia induced by the epinephrine in dogs anesthetized with ketamine

Este experimento teve por objetivo avaliar a viabilidade do emprego da levomepromazina no bloqueio da atividade arritmogênica da adrenalina, em cäes anestesiados pela quetamina. Para tal, foram utilizados 30 cäes adultos, machos e fêmeas, considerados sadios, com pesos compreendidos entre 7 e 14kg. Estes foram divididos em 3 grupos de 10 animais (G1, G2 e G3). Aos cäes de G1 foi administrada, por via intravenosa, adrenalina em doses de 3, 6, 9, 12 e 15µg/kg, em intervalos de 10 minutos. Deste grupo, foram colhidos o tempo de duraçäo do efeito da catecolamina (TA), estabelecido pela contagem da freqüência cardíaca e o número total de batimentos cardíacos de origem ectópica, produzidos pela adrenalina (ESV). Aos animais do G2, foi administrada soluçäo salina a 0,9 porcento, na dose de 0,2ml/kg, por via intravenosa, seguida, 10 minutos após, da injeçäo, pela mesma via, de quetamina, na dose de 2mg/kg. Decorridos 5 minutos, iniciou-se a infusäo contínua de quetamina, por via intravenosa, na dose de 0,2mg/kg/min. Aguardou-se 5 minutos e iniciou-se a adminstraçäo de adrenalina e colheita das variáveis, conforme protocolado para o G1. Aos animais do G3, aplicou-se a mesma metodologia, substituindo-se o placebo pela levomepromazina, administrada por via intravenosa, na dose de 1mg/kg. A análise dos resultados mostrou que a levomepromazina reduz a duraçäo do efeito da catecolamina e minimiza o aparecimento de batimentos cardíacos de origem ectópica. Os achados permitiram concluir que a levomepromazina é útil no bloqueio da arritmia produzida pela adrenalina em cäes anestesiados pela quetamina.

Experimental Models of Schizophrenia

Animal models can provide a useful tool for the study of some aspects of psychiatric disorders and their treatment. The four criteria for the evaluation of animal models of psychiatric disorders are as following : 1) similarity of inducing conditions 2) similarity of behavioral state 3) common underlying neurobiological mechanisms 4) reversal by clinically effective treatment techniques. Several animal models have been proposed for schizophrenia : phenylethylamine model, L-dopa model, hallucinogen model. cocaine model, amphetamine model, phencyclidine model, noradrenergic reward system lesion model, reticular stimulation model, social isolation model, conditioned avoidance reaction, catalepsy test, paw test, self-stimulation paradigms, latent inhibition paradigms, blocking paradigms, prepulse inhibition of the startle reflex, rodent interaction, social behavior in monkeys, hippocampal damage, high ambient pressure, and models using selective breeding. Among them, animals with bilateral lesion of the hippocampus may provide an adequate animal model for several symptoms of schizophrenia, and ketamine model can reproduce negative symptoms and cognitive deficits as well as positive symptoms of schizophrenia. In conclusion, no model of schizophrenia is entirely representative of the disease, and findings gleaned from model systems must be cautiously interpreted. Furthermore, the process of developing and validating animal models must work in concert with the process to identify reliable measures of human phenomenology.

Interacciones entre dopamina y glutamato en esquizofrenia / Interactions between dopamine and glutamate in schizophrenia

La hipótesis glutamatérgica de la esquizofrenia, que está recién en sus inicios, plantea que existe una alteración de la neurotransmisión glutamatérgica en esta enfermedad. La hipótesis se basa en los efectos psicoticomiméticos de la fenciclidina (PCF) y en las evidencias de actividad glutamatérgica anormal en pacientes esquizofrénicos. En este artículo se discute la posibilidad de que una deficiencia en la actividad de vías glutamatérgicas corticoestriatales pueda tener un papel fisiopatológico importante en la esquizofrenia. Se analizan las estrategias terapéuticas que se derivan de la hipótesis, como el empleo de agonistas glutamatérgicos y otros fármacos que pueden corregir la anormalidad planteada

El modelo de la fenciclidina en la esquizofrenia / The phencyclidine model of schizophrenia

La fenciclidina (PCP) produce psicosis muy similares a la esquizofrenia. Mientras las psicosis inducidas por anfetamina presentan sólo síntomas positivos como delirio y alucinaciones, las psicosis inducidas por PCP presentan tanto síntomas positivos como negativos (aplanamiento afectivo, retardo psicomotor, empobrecimiento del discurso). De este modo las psicosis anfetamínicas se ajustan a un modelo schneideriano y las psicosis por PCP a un modelo bleuleriano de esquizofrenia. La PCP se une selectivamente a un sitio de unión específico, el receptor a aminoácidos excitatorios N-metil-D-aspaertato (NMDA). Estos hallazgos sugieren que una disfunción de la neurotransmisión mediada por el receptor NMDA puede contribuir a la etiopatogenia de la esquizofrenia

Narcotics and their toxic behaviour

Narcotics have been a matter of great concern and pose increasing threats and dangers to humanity. The lack of awareness and knowledge about the abused drugs has further aggravated the situation. Various aspects of the addictive chemicals have been studied and the introductory notes on the major abused drugs, amphetamine 1, methamphetamine 2, 2, 5-dimethoxy-4-methylamphetamine 3, mescaline 4, cocaine 5, morphine 6, heroin 7, codeine 8, diazepam 9, pencyclidine 10, 1-piperidinocyclohexane cardonitrile 11, methaqualone 12, delta9- tetrahydrocannabinol 13 and methadone 14 have been presented. The pharmacological behaviour of the abused drugs are, as well, being discussed

Carbon-13 nuclear magnetic resonance spectra of some 4-substituted analogues of phencyclidine and thienylcyclidine

13C-Chemical shifts are reported for 1-[-1-phenylcylohexyl]-piperidine [PCP], 1-[1-[2-thienyl]cyclohexyl]piperidine [TCP] and a number of related analogues substituted at position 4- of the piperidine ring. Assignments are based on chemical shift theory comparison with related compounds signal multiplicities obtained from the analysis of distortionless enhancement by polarization transfer [DEPT] and attached proton transfer [APT] experiments in addition to 2D-NMR experiments. The substituents exert a similar influence on the piperidine ring carbons in the phenyl and thienyl series of compounds. The present study demonstrstes the value of 13C-NMR in identification purposes

Neurotransmisores y esquizofrenia / Neurotransmitters and schizophrenia

En la patologia esquizofrénica, los modelos bioquímicos explicativos mas comunes son: El de la Dopamina y el de la Fenciclidina. El neurotransmisor Dopamina actúa sobre los diversos receptores específicos, y la Fenciclidina sobre los llamados receptores de aminoácidos excitatorios. Otra hipótesis, como la de la Glicina o la de las Poliaminas, también tienen que ver con la acción sobre receptores de aminoacidos excitatorios. Esta revisión estudia algunos eventos neuroquímicos y neuropatológicos relacionados con los modelos mencionados. Conclusion: La esquizofrenia no puede ser explicada por un modelo simple, y mas bien es el resultado de una compleja interacción de disfunciones en los sistemas de neurotransmisión.

Interaction of amantadine and phencyclidine with the nicotinic acetylcholine receptor/channel from torpedo electric organ and philosamia ricini brain

In vitro interaction of amantadine and phencyclidine [PCP] with the nicotinic acetylcholine receptor/channel from Philosamia ricini brain and Torpedo electric organ was studied using [3H]PCP as channel probe. The results showed that binding of [3H]PCP to ionic channel of P. ricini brain was potentiated by amantadine, but the binding to ionic channel of Torpedo membranes was inhibited [Ki value is 2 mM]. Amantadine was suggested to act as agonist for ionic channel in insect brain. In addition, Scatchard analysis of the binding indicated at least two sites in P. ricini brain [a high affinity site with kd 5.3 mM and a low affinity site with kd 21.7 nm]. PCP inhibited the binding of [3H]PCP to ionic channel of P. ricini brain and Torpedo membranes with Ki values [0.013-0.016 mM] and 0.8 mM, respectively

The Vascular Effect of Ketamine Hydrochloride on The Isolated Rabbit Pulmonary ArteryC / 대한마취과학회지

Ketamine hydrochloride is a phencyclidine derivatives and dissociative anesthetics. Ketamine induce the pulmonary vasoconetrietion in vivo. This study was designed to deter- mine the direct effect of the ketamine on the rabbit pulmonary artery in vitro. Isolated pulmonary artery was precontracted with norepinephrine (NE) 10-7M in the 20 ml organ bath. Concentration of ketamine was gradually increased 10-5M, 10 4M and 10-3M at 10 minutes intervals. I divided forty three experimental speeimens into 5 groups : pulmonary artery with and without endothelium, pretreated with indomethacin, nitrow-L-arginine methyl ester(L-NAME) and methylene blue. The results were as follows : 1. Norepinephrine precontracted pulmonary arterial tone wss significantly decreased by ketamine(10-3M), and the relaxing percent were 81.0 19.3, 60.6 55.4 (Mean S.D.) in unrubbed and rubbed endothelium, respectively (p<0.05). 2. The changes of vascular tone in denuding and intact groups were not significantly different. 3. Vasorelaxation induced by ketamine was not related with nitric oxide(NO) synthase, cyclooxygenase and soluble guanylate cyclase. Ketamine induce relaxation of the rabbit pulmonary artery, especially at 10-3 M concentra- tion. The relaxing effect was not related with endothelium presence, nitric oxide synthase, cyclooxygenase and soluble guanylate cyclase pathways. This data suggest that the relaxing effect of ketamine was not associated with endothelium, Nitric oxide, prostacyclin and cyclic guanosinemonophosphate.