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1.
Basic Res Cardiol ; 117(1): 39, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35970954

RESUMO

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.


Assuntos
Isquemia Encefálica , COVID-19 , Precondicionamento Isquêmico Miocárdico , Acidente Vascular Cerebral , Animais , Educação , Isquemia , Resultado do Tratamento
2.
Neuropharmacology ; 138: 381-392, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29894771

RESUMO

Information on the distribution and biology of the G-protein coupled receptor 4 (GPR4) in the brain is limited. It is currently thought that GPR4 couples to Gs proteins and may mediate central respiratory sensitivity to CO2. Using a knock-in mouse model, abundant GPR4 expression was detected in the cerebrovascular endothelium and neurones of dorsal raphe, retro-trapezoidal nucleus locus coeruleus and lateral septum. A similar distribution was confirmed using RNAscope in situ hybridisation. In HEK293 cells, overexpressing GPR4, it was highly constitutively active at neutral pH with little further increase in cAMP towards acidic pH. The GPR4 antagonist NE 52-QQ57 effectively blocked GPR4-mediated cAMP accumulation (IC50 26.8 nM in HEK293 cells). In HUVEC which natively express GPR4, physiological acidification (pH 7.4-7.0) resulted in a cAMP increase by ∼55% which was completely prevented by 1 µM NE 52-QQ57. The main extracellular organic acid, l-lactic acid (LL; 1-10 mM), suppressed pH dependent activation of GPR4 in HEK293 and HUVEC cells, suggesting allosteric negative modulation. In unanaesthetised mice and rats, NE 52-QQ57 (20 mg kg-1) reduced ventilatory response to 5 and 10% CO2. In anaesthetised rats, systemic administration of NE 52-QQ57 (up to 20 mg kg-1) had no effect on hemodynamics, cerebral blood flow and blood oxygen level dependent responses. Central administration of NE 52-QQ57 (1 mM) in vagotomised anaesthetised rats did not affect CO2-induced respiratory responses. Our results indicate that GPR4 is expressed by multiple neuronal populations and endothelium and that its pH sensitivity is affected by level of expression and LL. NE 52-QQ57 blunts hypercapnic response to CO2 but this effect is absent under anaesthesia, possibly due to the inhibitory effect of LL on GPR4.


Assuntos
Encéfalo/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , AMP Cíclico/metabolismo , Endotélio/citologia , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Células HEK293 , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/administração & dosagem , Ácido Láctico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxidiazóis/farmacologia , Oxigênio/sangue , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Respiração
3.
Neurochem Res ; 40(12): 2386-93, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25837670

RESUMO

Astrocytes occupy a strategic position in the brain where they can act as an interface between neurones and blood vessels, and neurones and the cerebro-spinal fluid. This location is ideal for functioning as interoceptors, as they may sense changes in brain microenvironment and contribute to the adaptive homeostatic responses coordinated by neuronal networks. Here we briefly review some of the recent evidence, which implicates the involvement of astrocytes in the central nervous control of breathing, sympathetic tone and blood glucose levels. L-lactate appears a potentially crucial signaling molecule in the communication between astrocytes and neurones. Based on the available evidence, we conclude that astrocytes contribute to the homeostasis by playing a significant role in the brain's interoceptive mechanisms.


Assuntos
Astrócitos/metabolismo , Astrócitos/fisiologia , Encéfalo/fisiologia , Microambiente Celular/fisiologia , Animais , Química Encefálica , Humanos
4.
Nat Commun ; 5: 3284, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24518663

RESUMO

Astrocytes produce and release L-lactate as a potential source of energy for neurons. Here we present evidence that L-lactate, independently of its caloric value, serves as an astrocytic signalling molecule in the locus coeruleus (LC). The LC is the principal source of norepinephrine to the frontal brain and thus one of the most influential modulatory centers of the brain. Optogenetically activated astrocytes release L-lactate, which excites LC neurons and triggers release of norepinephrine. Exogenous L-lactate within the physiologically relevant concentration range mimics these effects. L-lactate effects are concentration-dependent, stereo-selective, independent of L-lactate uptake into neurons and involve a cAMP-mediated step. In vivo injections of L-lactate in the LC evokes arousal similar to the excitatory transmitter, L-glutamate. Our results imply the existence of an unknown receptor for this 'glio-transmitter'.


Assuntos
Neurônios Adrenérgicos/metabolismo , Astrócitos/metabolismo , Ácido Láctico/metabolismo , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Animais , Neuroglia/metabolismo , Neurônios/metabolismo , Ratos , Transdução de Sinais
5.
Bull Exp Biol Med ; 152(4): 389-91, 2012 Feb.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-22803093

RESUMO

We measured the concentration of ATP in the posterior cingulum bundle of Sprague-Dawley rats during electrical stimulation of the negative emotiogenic zone in the ventromedial hypothalamus. Electrostimulation of the ventromedial hypothalamus in animals was accompanied by an increase in systolic and diastolic blood pressure, which illustrates the autonomic response to this treatment. Variations in BP of rats were followed by an increase in ATP content in the posterior cingulum bundle. After stimulation of the ventromedial hypothalamus, ATP concentration in the cingulum bundle reached the maximum levels of 1.3±0.3 µM (n=4) and 1.67±0.43 µM (n=10) and remained high for 42.6±7.5 sec. The enhanced release of ATP in the cingulate region of the brain is probably related to the involvement of this structure into emotional reactions. ATP plays a role of the major energy source and signal molecule, which provides the adequate biochemical and physiological processes and cell-to-cell interaction in CNS upon the exposure to negative emotiogenic factors.


Assuntos
Trifosfato de Adenosina/metabolismo , Giro do Cíngulo/fisiologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Animais , Pressão Sanguínea , Estimulação Elétrica , Emoções/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
6.
Cell Death Dis ; 3: e335, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22739987

RESUMO

Loss of the mitochondrial protease HtrA2 (Omi) in mice leads to mitochondrial dysfunction, neurodegeneration and premature death, but the mechanism underlying this pathology remains unclear. Using primary cultures from wild-type and HtrA2-knockout mice, we find that HtrA2 deficiency significantly reduces mitochondrial membrane potential in a range of cell types. This depolarisation was found to result from mitochondrial uncoupling, as mitochondrial respiration was increased in HtrA2-deficient cells and respiratory control ratio was dramatically reduced. HtrA2-knockout cells exhibit increased proton translocation through the ATP synthase, in combination with decreased ATP production and truncation of the F1 α-subunit, suggesting the ATP synthase as the source of the proton leak. Uncoupling in the HtrA2-deficient mice is accompanied by altered breathing pattern and, on a cellular level, ATP depletion and vulnerability to chemical ischaemia. We propose that this vulnerability may ultimately cause the neurodegeneration observed in these mice.


Assuntos
Trifosfato de Adenosina/metabolismo , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , ATPases Translocadoras de Prótons/metabolismo , Serina Endopeptidases/genética , Sequência de Aminoácidos , Animais , Respiração Celular , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Dados de Sequência Molecular , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Serina Endopeptidases/metabolismo
7.
Exp Physiol ; 96(1): 40-50, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21041318

RESUMO

We briefly review the current literature where optogenetics has been used to study various aspects of astrocyte physiology in vitro and in vivo. This includes both genetically engineered Ca(2+) sensors and effector proteins, such as channelrhodopsin. We demonstrate how the ability to target astrocytes with cell-specific viral vectors to express optogenetic constructs helped to unravel some previously unsuspected roles of these inconspicuous cells.


Assuntos
Astrócitos/fisiologia , Engenharia Genética/métodos , Óptica e Fotônica/métodos , Rodopsina/fisiologia , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Luz , Rede Nervosa/fisiologia
8.
Biochem Soc Trans ; 35(Pt 5): 1264-8, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17956326

RESUMO

The purine nucleotide ATP mediates several distinct forms of sensory transduction in both the peripheral and central nervous systems. These processes share common mechanisms that involve the release of ATP to activate ionotropic P2X and/or metabotropic P2Y receptors. Extracellular ATP signalling plays an important role in ventilatory control, mediating both peripheral and central chemosensory transduction to changes in arterial levels of oxygen and carbon dioxide. New data also suggest that extracellular ATP may play an important role in mediating certain neurophysiological responses to systemic inflammation. Here, we propose the novel concept that both peripheral and central neurophysiological effects of ATP may contribute to alterations in ventilatory control during inflammatory pathophysiological states.


Assuntos
Trifosfato de Adenosina/fisiologia , Respiração , Animais , Humanos , Inflamação/fisiopatologia
9.
Acta Physiol Scand ; 183(2): 151-9, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15676056

RESUMO

AIMS: The aim of this study was to test whether oral pre-treatment with rosuvastatin at a dosage giving clinically relevant plasma concentrations protects the myocardium against ischaemia/reperfusion injury and to investigate the involvement of nitric oxide (NO) and neutrophil infiltration. METHODS: Pigs were given placebo (n = 7), rosuvastatin (80 mg day(-1), n =7), rosuvastatin (160 mg day(-1), n = 7) or pravastatin (160 mg day(-1), n = 7) orally for 5 days before being subjected to coronary artery ligation and reperfusion. An additional group was given rosuvastatin 160 mg day(-1) and a nitric oxide synthase (NOS) inhibitor. RESULTS: Rosuvastatin 80 and 160 mg day(-1) resulted in plasma concentrations of 2.6 +/- 0.7 and 5.6 +/- 1.0 ng mL(-1), respectively. Serum cholesterol was not affected. Rosuvastatin 160 mg day(-1) and pravastatin limited the infarct size from 82 +/- 3% of the area at risk in the placebo group to 61 +/- 3% (P < 0.05), and to 61 +/- 2% (P < 0.05) respectively. Rosuvastatin 80 mg day(-1) limited the infarct size to 69 +/- 2%, however, this effect was not statistically significant. Rosuvastatin 160 mg day(-1) attenuated neutrophil infiltration in the ischaemic/reperfused myocardium. The protective effect of rosuvastatin 160 mg day(-1) was abolished by NOS inhibition. The expression of NOS2 and NOS3 in the myocardium did not differ between the groups. CONCLUSIONS: Oral pre-treatment with rosuvastatin limited infarct size following ischaemia/reperfusion without affecting cholesterol levels. The cardioprotective effect is suggested to be dependent on maintained bioactivity of NO, without influencing NOS expression.


Assuntos
Colesterol/sangue , Fluorbenzenos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/metabolismo , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Feminino , Fluorbenzenos/sangue , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Miocárdio/enzimologia , Infiltração de Neutrófilos/fisiologia , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Peroxidase/metabolismo , Pravastatina/administração & dosagem , Pirimidinas/sangue , Rosuvastatina Cálcica , Sulfonamidas/sangue , Suínos
10.
Neuroscience ; 121(2): 411-9, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14521999

RESUMO

A large body of evidence suggests that nitric oxide (NO) and ATP act as neurotransmitters in the regulatory mechanisms concerning several autonomic functions at the level of both the hypothalamus and the brain stem. In the present study, we investigated whether neuronal NO synthase containing neurones also express P2X(2) receptor subunit of the ATP-gated ion channel via double-labelling fluorescence immunohistochemistry. Our data demonstrate that a high percentage of neuronal NO synthase-immunoreactive neurones are also P2X(2)-immunoreactive in the rostral ventrolateral medulla (98%) and supraoptic nucleus of the hypothalamus (92%). Significant numbers of neuronal NO synthase-immunoreactive neurones are also P2X(2)-immunoreactive in the subpostremal (48%) and commissural (65%) subdivisions of the nucleus tractus solitarius. In the caudal ventrolateral medulla and raphe obscurus, 96% and 89%, respectively, of neuronal NO synthase containing neurones also express P2X(2) receptor subunit. In contrast to the supraoptic nucleus, there was a lower percentage of co-localisation between NO synthase and P2X(2) receptor subunit in the paraventricular nucleus of the hypothalamus. In summary, this study demonstrates for the first time that there is a widespread co-localisation of neuronal NO synthase and P2X(2) receptor subunit in the hypothalamus and brain stem of the rat. Further studies are required to elucidate whether NO and ATP functionally interact within the hypothalamus and the brain stem.


Assuntos
Tronco Encefálico/citologia , Hipotálamo/citologia , Neurônios/metabolismo , Óxido Nítrico Sintase/metabolismo , Receptores Purinérgicos P2/metabolismo , Animais , Contagem de Células , Imunofluorescência , Masculino , Fotomicrografia , Subunidades Proteicas/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptores Purinérgicos P2X2
11.
Neuroreport ; 12(15): 3395-400, 2001 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-11711893

RESUMO

This study tested the hypothesis that during hypercapnia partial removal of a tonic GABA-mediated inhibition contributes to the increase in activity of the ventrolateral medulla (VLM) inspiratory neurones. Extracellular recordings were taken from 22 inspiratory neurones in the VLM of rats anaesthetised with pentobarbitone and artificially ventilated. It was found that during hypercapnia, changes in the discharge pattern (i.e. an increase in the discharge frequency during the neurone's normally active phase) and firing frequency of the VLM inspiratory neurones were similar to those evoked by GABA(A) receptor antagonist bicuculline methiodide (BMI, 10 mM, 20 nA), applied ionophoretically in conditions of normocapnia. During hypercapnia BMI (20 nA) failed to evoke a further increase in firing of these neurones. This suggests that CO2-evoked activation of VLM inspiratory neurones may involve a withdrawal in part of a tonic GABA(A) receptor-mediated inhibition. This disinhibition may play a role in the hypercapnia-induced increase in ventilatory activity.


Assuntos
Células Quimiorreceptoras/metabolismo , Bulbo/metabolismo , Neurônios/metabolismo , Receptores de GABA-A/metabolismo , Centro Respiratório/metabolismo , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Bicuculina/farmacologia , Dióxido de Carbono/sangue , Células Quimiorreceptoras/efeitos dos fármacos , Estimulação Elétrica , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Centro Respiratório/citologia , Centro Respiratório/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
12.
Basic Res Cardiol ; 96(5): 454-62, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11605992

RESUMO

It has previously been shown that endothelin (ET) receptor antagonists limit myocardial ischaemia/reperfusion (I/R) injury. The mechanism behind this effect is still unclear. The aim of this study was to elucidate the possible relationship between cardioprotection by an ET(A) receptor antagonist and inhibition of neutrophil accumulation or activation in the myocardium determined as myeloperoxidase (MPO) activity during I/R. Anaesthetised pigs were subjected to 45 min ischaemia by ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Infiltration of MPO-containing cells, presumably neutrophils, into the ischaemic area was confirmed with an immunohistochemical technique using antibodies against porcine MPO. Vehicle (n = 7) or the selective ET(A) receptor antagonist LU 135252 (LU; n = 7) were given into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. There were no significant differences in LAD flow, mean arterial pressure, heart rate, or rate pressure product between the groups during I/R. The area at risk was similar in the two groups. LU reduced the final infarct size to 40+/-6% of the area at risk compared to 80+/-6% in the vehicle group (P < 0.001). Endothelin-like immunoreactivity increased 2-fold in the ischaemic area in the vehicle group (P < 0.01), but not in the group given LU. MPO activity was higher (2.5x) in the ischaemic than in the non-ischaemic myocardium of the vehicle group. The MPO activity in the ischaemic myocardium was significantly lower in the group given LU (7.0+/-1.2 units g(-1)) than in the vehicle group (14.2+/-1.9 units g(-1); P < 0.01). There was a significant correlation between the infarct size and MPO activity (P < 0.01, r = 0.68). In conclusion, local administration of the selective ET(A) receptor antagonist LU during the last period of ischaemia and early reperfusion reduces the extent of myocardial necrosis and MPO activity. This suggests that LU may exert its cardioprotective effect by inhibiting neutrophil-mediated injury.


Assuntos
Antagonistas dos Receptores de Endotelina , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Peroxidase/metabolismo , Animais , Anticorpos , Pressão Sanguínea , Cardiotônicos/farmacologia , Feminino , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/imunologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Necrose , Neutrófilos/enzimologia , Peroxidase/análise , Fenilpropionatos/farmacologia , Pressão Propulsora Pulmonar , Pirimidinas/farmacologia , Receptor de Endotelina A , Receptores de Endotelina/análise , Receptores de Endotelina/imunologia , Suínos
13.
Neuroimmunomodulation ; 9(1): 13-22, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11435748

RESUMO

OBJECTIVE: Peripheral afferents play an important role in fever. In the present study, we investigated the role of capsaicin-sensitive afferents in fever and cytokine responses during systemic (induced by intraperitoneal lipopolysaccharide, LPS) and local (induced by injection of Freund's incomplete adjuvant, FIA, into the paw) inflammation. METHODS: Fevers in rats (8-10 weeks of age) whose capsaicin-sensitive afferents were depleted by neonatal capsaicin (50 mg/kg) treatment were compared to those of rats treated as neonates with vehicle. To investigate a possible involvement of cytokines, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured during LPS- and FIA-induced fever in rats after capsaicin-induced desensitization. Body temperature was measured by biotelemetry. IL-6 and TNF bioactivities in plasma were determined using bioassays. RESULTS: The initial but not the late phase of LPS (50 microg/kg)-induced fever was markedly higher (approximately 1.0 degree C) in rats whose capsaicin-sensitive neurons were destroyed by neonatal capsaicin treatment. Capsaicin-induced desensitization also resulted in significantly higher plasma levels of IL-6 and TNF 1 but not 4 h after LPS challenge. In contrast, the day after injection with FIA (0.1 ml), rats treated with capsaicin had significantly lower body temperatures compared with vehicle-treated animals. No differences were found in plasma levels of IL-6 and TNF between capsaicin- and vehicle-treated animals in response to FIA. CONCLUSIONS: These data indicate that the role of capsaicin-sensitive afferents in fever depends on the type of inflammatory response. During systemic inflammation, capsaicin-sensitive afferents may be involved in modulating fever by regulating the levels of pyrogenic cytokines. During local inflammation, the late phase of fever is partially mediated via capsaicin-sensitive afferents.


Assuntos
Capsaicina/farmacologia , Citocinas/metabolismo , Febre/etiologia , Inflamação/fisiopatologia , Neurônios Aferentes/fisiologia , Nociceptores/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Animais Recém-Nascidos , Atrofia , Capsaicina/toxicidade , Citocinas/sangue , Denervação , Comportamento Exploratório/fisiologia , Febre/fisiopatologia , , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/toxicidade , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/imunologia , Injeções Intraperitoneais , Interleucina-6/sangue , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Pulmão/inervação , Pulmão/patologia , Neurônios Aferentes/efeitos dos fármacos , Peritonite/induzido quimicamente , Peritonite/complicações , Peritonite/imunologia , Peritonite/fisiopatologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/análise , Bexiga Urinária/inervação , Bexiga Urinária/patologia
14.
Am J Physiol Heart Circ Physiol ; 280(3): H1105-12, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11179053

RESUMO

The interaction between the cardioprotective effect of endothelin (ET) receptor blockade and nitric oxide (NO) during ischemia-reperfusion injury was investigated. Anesthetized pigs were subjected to 45 (protocol 1) or 30 min (protocol 2) coronary artery ligation and 4 h reperfusion. In protocol 1, five groups were given vehicle, the ET(A) receptor antagonist LU-135252 (LU), the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NNA), L-NNA in combination with LU, or L-NNA in combination with the NO precursor L-arginine (L-Arg) and LU intravenously before ischemia. In protocol 2, two groups were given vehicle or L-NNA. In protocol 1, the infarct size (IS) was 79 +/- 5% of the area at risk in the vehicle group and 93 +/- 2% in the L-NNA group. LU reduced the IS to 43 +/- 7% (P < 0.001). The cardioprotective effect of LU was abolished in the presence of L-NNA (IS 76 +/- 6%), whereas addition of L-Arg restored its cardioprotective effect (IS 56 +/- 2%; P < 0.05 vs. vehicle and L-NNA + LU groups). In protocol 2, the IS was 49 +/- 6% in the vehicle group and 32 +/- 4% in the L-NNA group (P = not significant). Myocardial ET-like immunoreactivity (ET-LI) increased in the vehicle group of protocol 1. ET-LI in the ischemic-reperfused myocardium was lower in the groups given LU (P < 0.01) and L-NNA + L-Arg + LU (P < 0.05) but not in the group given L-NNA + LU compared with the vehicle group. These results suggest that the cardioprotective effect of the ET(A) receptor antagonist is mediated via a mechanism related to NO.


Assuntos
Antagonistas dos Receptores de Endotelina , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Fenilpropionatos/farmacologia , Pirimidinas/farmacologia , Animais , Pressão Sanguínea , Circulação Coronária , Endotelina-1/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Frequência Cardíaca , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/mortalidade , Traumatismo por Reperfusão Miocárdica/mortalidade , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Nitroarginina/farmacologia , Receptor de Endotelina A , Taxa de Sobrevida , Suínos
15.
J Cardiovasc Pharmacol ; 36(3): 405-12, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10975600

RESUMO

It has previously been shown that endothelin (ET)-receptor antagonists protect the myocardium from ischemia and reperfusion (I/R) injury. The mechanism behind this effect is unclear. The aim of this study was to elucidate the possible interaction between ET(A)-receptor antagonism and nitric oxide (NO) during I/R. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Vehicle (n = 7), the ET(A)-receptor antagonist LU 135252 (LU; 0.1 mg/kg, n = 7), the combination of LU and the NO precursor L-arginine (15 mg/kg, n = 7; LU + L-arg), the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 0.2 mg/kg, n = 6), or the combination of LU and L-NMMA (LU + L-NMMA; n = 6) were injected into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in coronary flow, pulmonary capillary wedge pressure, mean arterial pressure, or heart rate between the groups before ischemia or at the end of reperfusion. The area at risk was similar in all five groups. The infarct size of the vehicle group was 79 +/- 6% of the area at risk. LU and LU + L-arginine (L-arg) reduced the infarct size to 39 +/- 6% and 35 +/- 8%, respectively (p < 0.001 vs. vehicle). L-NMMA completely prevented the infarct-limiting effect of LU. Thus the infarct size in the LU + L-NMMA group was 83 +/- 4% (p < 0.001 vs. LU alone); L-NMMA did not affect infarct size per se (79 +/- 4%). ET immunoreactivity increased threefold in the I/R myocardium of the vehicle group. The increase in ET immunoreactivity was significantly attenuated in the LU and LU + L-arg groups (p < 0.001), but not in the groups given L-NMMA or LU + L-NMMA. In conclusion, ET(A)-receptor blockade results in cardioprotection and attenuation of the increase in myocardial ET levels after I/R. Both effects were inhibited by NO synthase blockade, suggesting that they are dependent on maintained production of NO.


Assuntos
Antagonistas dos Receptores de Endotelina , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Óxido Nítrico/biossíntese , Fenilpropionatos/farmacologia , Pirimidinas/farmacologia , Animais , Endotelinas/análise , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Receptor de Endotelina A , Suínos , ômega-N-Metilarginina/farmacologia
16.
Neuroimmunomodulation ; 8(1): 8-12, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10859482

RESUMO

Interleukin (IL)-11 is a member of the gp130 family of cytokines. In contrast to IL-6 (another gp130 cytokine), IL-11 does not induce fever in humans. In the present study, the effect of recombinant human IL-11 (hrIL-11) injected intracerebroventricularly on body temperature of afebrile and febrile rats was studied. Results showed that: (i) hrIL-11 in doses of 5, 50 and 500 ng injected into the cerebral ventricles does not alter body temperature in rats; (ii) febrile response induced by intraperitoneal injection of E. coli endotoxin (50 microg/kg) was initiated more rapidly in rats injected with 500 ng of hrIL-11 in the cerebral ventricles, and (iii) the enhancement of the initial phase of fever induced by hrIL-11 was not accompanied by changes in plasma concentrations of IL-6 and tumor necrosis factor (TNF). These results indicate that hrIL-11 is not pyrogenic when administered into the brain ventricles. The data obtained also demonstrate that central application of hrIL-11 alters body temperature in conditions of pyrogenic stimulation, but that this effect is not due to the alterations in plasma concentrations of IL-6 or TNF. These data suggest that during the development of the systemic inflammatory response, activation of gp130 subunit becomes effective in altering body temperature.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/imunologia , Febre/imunologia , Interleucina-11/farmacologia , Animais , Febre/induzido quimicamente , Células Híbridas , Hipotálamo/fisiologia , Injeções Intraventriculares , Interleucina-6/sangue , Lipopolissacarídeos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Organismos Livres de Patógenos Específicos , Terceiro Ventrículo , Fator de Necrose Tumoral alfa/metabolismo
17.
Basic Res Cardiol ; 95(2): 127-36, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10826505

RESUMO

The interstitial accumulation of adenine nucleotide breakdown products (ANBP) in the myocardium during ischemia has been shown to provide a useful index of the ischemic injury, whereas reperfusion ANBP washout rate has been regarded as an index of reperfusion damage. The purpose of this study was, using cardiac microdialysis, to examine in the rat model of regional ischemia/reperfusion the relationship between the duration of ischemia and these indices and to assess the profile of interstitial ATP concentrations and the beneficial effects of ischemic preconditioning (IP). The rats underwent 10, 20, 30 or 40 min of coronary artery occlusion and 50 min of reperfusion. Regional ischemia, with its duration, provoked a progressive increase in dialysate ANBP in the ischemic zone. The rate of purine washout during reperfusion exponentially declined with an increase in duration of the ischemic period. IP, induced by three 5-min episodes of ischemia, each separated by 5 min of reperfusion, significantly reduced the accumulation of ANBP during the 30-min period of sustained ischemia and resulted in a marked acceleration of reperfusion ANBP washout, indicating the improvement of postischemic microcirculation. These effects were suggested to be, at least in part, responsible for the infarct size limitation observed. Using the relationship between the duration of ischemia and ANBP washout rate, it could be demonstrated that IP produced similar facilitation of purine washout as shortening of the ischemic period in nonpreconditioned rats from 30 to approximately 7 min. Regional 20-min ischemia induced an early peak increase in interstitial fluid ATP which correlated with the maximal incidence of ventricular arrhythmias, whereas IP abolished both ATP release and arrhythmias during the sustained ischemia. These findings suggest that ATP may be an important mediator of ischemia-induced ventricular arrhythmias.


Assuntos
Trifosfato de Adenosina/análise , Precondicionamento Isquêmico , Isquemia Miocárdica/metabolismo , Reperfusão Miocárdica , Miocárdio/química , Trifosfato de Adenosina/metabolismo , Animais , Arritmias Cardíacas/etiologia , Hemodinâmica , Masculino , Microdiálise , Purinas/metabolismo , Ratos , Ratos Wistar
18.
Regul Pept ; 88(1-3): 33-9, 2000 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-10706950

RESUMO

The influence of bombesin (1 microg/0.1 ml artificial cerebrospinal fluid) on neuronal thermosensitivity of the preoptic area of the anterior hypothalamus in brain slices of 5- (n = 7 neurons) and 10-day-old (n = 36 neurons) Muscovy ducks (Cairina moschata) was investigated. Similar to adult mammals, most of the neurons investigated increased the firing rate (FR) after bombesin application. Changes in FR were not related to changes in thermal coefficient (TC). The neurons react to bombesin also under synaptic blockade. The bombesin-induced effect on TC (increase or decrease in nearly the same number of neurons, e.g. nine neurons increased and ten decreased TC in 10-day-old ducklings) in the postnatal bird neurons investigated was different from the results described in adult mammals, where the main reaction to bombesin was an increase of TC in warm-sensitive and temperature-insensitive-neurons and a transformation of temperature-insensitive-neurons into warm-sensitive ones. This may be related to the assumption that during early ontogeny, body functions react to exogenous and endogenous factors nonspecifically. It is to speculate, that later, probably at the end of embryonic development or during the early postnatal period, the reactivity of these functions changes qualitatively, so that the reaction of an individual function to different factors becomes specific (ultimately adaptive).


Assuntos
Núcleo Hipotalâmico Anterior/efeitos dos fármacos , Bombesina/farmacologia , Neurônios/efeitos dos fármacos , Área Pré-Óptica/efeitos dos fármacos , Animais , Núcleo Hipotalâmico Anterior/citologia , Núcleo Hipotalâmico Anterior/fisiologia , Patos , Neurônios/fisiologia , Área Pré-Óptica/citologia , Área Pré-Óptica/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Temperatura
19.
Am J Physiol ; 275(3): R754-61, 1998 09.
Artigo em Inglês | MEDLINE | ID: mdl-9728072

RESUMO

Bacterial endotoxin induces fever by causing the release of interleukin (IL)-1beta into the circulation or the brain. IL-1beta is believed to mediate fever via triggering the production and/or release of IL-6 in the hypothalamus. The present study examined whether IL-1beta and IL-6 in the hypothalamus of the rat are also involved in fever during bacterial sepsis caused by cecal ligation and puncture (CLP). CLP induces fever for 2 days. Polyclonal rabbit antibody against rat IL-1beta (anti-IL-1beta, 2 microg/microl) or control rabbit IgG (2 microg/microl) was unilaterally microinjected into the hypothalamus of rats immediately after or 24 h after CLP or sham-CLP surgery. Anti-IL-1beta injected 24 h after CLP (when fever was already present) or sham-CLP surgery did not affect fever. Microinjection of anti-IL-1beta into the hypothalamus immediately after surgery caused a significant decrease in body temperature during the night after CLP surgery and a 48% reduction of fever on the following day. Although blood plasma levels of IL-6 were significantly elevated 1.5, 6, 24, and 48 h after CLP surgery, there were no differences in IL-6 concentrations in the extracellular fluid of the anterior hypothalamus (collected by push-pull perfusion). These data suggest that fever due to bacterial sepsis is initiated by IL-1beta within the hypothalamus, and this febrile response, unlike endotoxin-induced fever, is not accompanied by elevation in the hypothalamic concentration of IL-6.


Assuntos
Ceco/cirurgia , Febre/fisiopatologia , Hipotálamo/fisiopatologia , Interleucina-1/fisiologia , Sepse/fisiopatologia , Animais , Infecções Bacterianas/etiologia , Infecções Bacterianas/fisiopatologia , Ceco/microbiologia , Febre/etiologia , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/análise , Injeções Intraventriculares , Interleucina-1/administração & dosagem , Interleucina-1/antagonistas & inibidores , Cinética , Ligadura , Masculino , Microinjeções , Punções , Coelhos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Sepse/etiologia , Distribuição Tecidual
20.
Prehosp Disaster Med ; 12(1): 41-6, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-10166374

RESUMO

INTRODUCTION: There has been relatively little attention paid to the mid- and long-term effects of large-scale disasters, particularly their effects on children and young people. At the present time, the impact of the Chernobyl catastrophe on the daily lives of the affected population may include one of strong psychological stress due to uncertainty about ultimate health outcomes. Persons in the Chernobyl region in specific areas of low contamination may be affected similarly. This investigation assesses radiation concerns and attitudes about health and government information, nine years after the disaster, in a group of adults and adolescents residing in a relatively uncontaminated village in the Chernobyl area. METHODS: Questionnaires were administered to 94 adults and 50 adolescents. Items assessed beliefs about extent of radiation exposure, health concerns regarding oneself and family members, past and current preoccupation about the disaster, and trust in the accuracy of government information about health effects. RESULTS: Considerable uncertainty was demonstrated in both adults and adolescents about the extent of their and their families exposure to radiation. Marked distrust of past and current government information about health effects was evident. A large proportion of subjects reported that they still thought frequently about the Chernobyl accident. They worried about health problems related to radiation exposure whenever they or their family members exhibited physical symptoms or complaints, and they urged family members to go to a medical clinic for evaluation to assess these symptoms. CONCLUSIONS: The extent of long-term concerns about the personal and family health effects of the Chernobyl disaster in this population residing in a relatively uncontaminated village is striking: the psychological impact on adolescents is considerable. The stress generated is maintained by the realistic uncertainty about the ultimate health consequences to the overall population as a result of radiation exposure and distrust in government information about contamination levels in this particular village. The level of stress and its effects on physical and mental health may increase over time if there is a rise in morbidity in the area. The continuing health needs of the extremely large population affected by the Chernobyl disaster need to be addressed.


Assuntos
Atitude , Liberação Nociva de Radioativos/psicologia , Poluentes Radioativos/análise , Adolescente , Adulto , Atitude Frente a Saúde , Feminino , Governo , Humanos , Masculino , Pessoa de Meia-Idade , República de Belarus , Ucrânia
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