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1.
J Enzyme Inhib Med Chem ; 35(1): 622-628, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037900

RESUMO

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (KIs of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazinas/farmacologia , Compostos Organometálicos/farmacologia , Sulfonamidas/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/química
2.
Nat Commun ; 10(1): 5229, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745077

RESUMO

A rapid and deep decarbonization of power supply worldwide is required to limit global warming to well below 2 °C. Beyond greenhouse gas emissions, the power sector is also responsible for numerous other environmental impacts. Here we combine scenarios from integrated assessment models with a forward-looking life-cycle assessment to explore how alternative technology choices in power sector decarbonization pathways compare in terms of non-climate environmental impacts at the system level. While all decarbonization pathways yield major environmental co-benefits, we find that the scale of co-benefits as well as profiles of adverse side-effects depend strongly on technology choice. Mitigation scenarios focusing on wind and solar power are more effective in reducing human health impacts compared to those with low renewable energy, while inducing a more pronounced shift away from fossil and toward mineral resource depletion. Conversely, non-climate ecosystem damages are highly uncertain but tend to increase, chiefly due to land requirements for bioenergy.


Assuntos
Poluição do Ar/prevenção & controle , Dióxido de Carbono/antagonistas & inibidores , Ecossistema , Gases de Efeito Estufa/antagonistas & inibidores , Energia Renovável , Poluição do Ar/análise , Dióxido de Carbono/análise , Fontes de Energia Elétrica , Aquecimento Global , Efeito Estufa , Gases de Efeito Estufa/análise , Humanos
3.
Rev. clín. esp. (Ed. impr.) ; 219(4): 208-217, mayo 2019. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-186535

RESUMO

Los inhibidores del cotransportador sodio-glucosa tipo 2 han cambiado el concepto que se tenía de los efectos que ejercen los fármacos hipoglucemiantes sobre la insuficiencia cardiaca (IC). Es la primera vez que un grupo terapéutico modifica la evolución de la IC. Sus efectos trascienden al control glucémico, postulándose diferentes teorías para justificar estos beneficios. En este artículo analizamos la influencia que tienen sobre la IC los distintos grupos farmacológicos utilizados en el tratamiento de la diabetes mellitus tipo 2, y planteamos el posible mecanismo de acción asociado con los beneficios aportados por estos fármacos. Somos de la opinión de que este beneficio sobre la IC es secundario a su efecto diurético, en concreto a una actividad muy parecida a la de los inhibidores del dióxido de carbono. Pensamos que se trata de una teoría novedosa que explica el mecanismo de acción. No hemos encontrado en la literatura ningún artículo que desarrolle de manera tan precisa dicho mecanismo


Sodium-glucose cotransporter-2 inhibitors have changed the concept of the effects that hypoglycemic drugs have on hearth failure (HF). For the first time, a therapeutic group has modified the evolution of HF. Its effect goes beyond glycemic control, and different theories have been postulated to justify this benefit. In the article we sent, we analyze the influence of the different pharmacological groups used in type 2 diabetes mellitus on HF, and we present the theory of the mechanism of action associated with the benefit of these drugs. In our opinion, this benefit in HF is secondary to its diuretic effect, specifically an effect very similar to carbon dioxide inhibitors. We think that our theory is novel, explains the mechanism of action and we have not found in the literature any article that explains the mechanism of action in such a precise way


Assuntos
Humanos , Insuficiência Cardíaca/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Acetazolamida/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Diuréticos/uso terapêutico , Dióxido de Carbono/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Interações Medicamentosas
4.
Crit Care ; 23(1): 426, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888721

RESUMO

BACKGROUND: Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon-especially when CO2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2 reactivity (CVR) and regional brain oxygenation (rSO2). METHODS: In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2 was determined during step changes of PaCO2 between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2 alterations were determined for each flow mode. Each patient served as her own control. RESULTS: MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO2 slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8-16.9] and 10.4 cm/s/mmHg [CI 7.9-13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg, p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO2 and ΔMCAv was less pronounced during non-pulsatile flow. CONCLUSIONS: Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO2/ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed. TRIAL REGISTRATION: The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).


Assuntos
Dióxido de Carbono/metabolismo , Circulação Cerebrovascular/fisiologia , Fluxo Pulsátil/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Idoso , Dióxido de Carbono/antagonistas & inibidores , Estudos de Casos e Controles , Circulação Cerebrovascular/efeitos dos fármacos , Cérebro/irrigação sanguínea , Oxigenação por Membrana Extracorpórea/métodos , Oxigenação por Membrana Extracorpórea/normas , Feminino , Humanos , Hipercapnia/metabolismo , Hipercapnia/fisiopatologia , Hipocapnia/metabolismo , Hipocapnia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pressão Parcial , Estudos Prospectivos , Fluxo Pulsátil/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Suíça
5.
J Biomol Screen ; 21(4): 363-71, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26701099

RESUMO

Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically.


Assuntos
Alcaloides/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Células Epiteliais/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Macrófagos/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/agonistas , Peptídeos Catiônicos Antimicrobianos/antagonistas & inibidores , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Dióxido de Carbono/toxicidade , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Drosophila melanogaster/citologia , Drosophila melanogaster/imunologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Expressão Gênica , Genes Reporter , Humanos , Hipercapnia/prevenção & controle , Interleucina-6/genética , Interleucina-6/imunologia , Luciferases/genética , Luciferases/metabolismo , Macrófagos/citologia , Macrófagos/imunologia
6.
Acc Chem Res ; 47(7): 2052-62, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24785941

RESUMO

Conspectus This Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and π-π interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host-guest chemistry in water. We discovered that CB[n] homologues (CB[7] and CB[8]) display remarkably high binding affinity (Ka up to 10(17) M(-1)) and selectivity (ΔΔG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host-guest systems. The CB[7]·adamantaneammonium ion complex, which is particularly privileged (Ka = 4.2 × 10(12) M(-1)), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host-guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene-arylene foldamers and cationic calix[4]arenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves. Many guests display large pKa shifts within their CB[n]-guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB[7] toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB[7] from gold nanoparticles passivated with hexanediammonium ion·CB[7] complexes and thereby trigger cytotoxicity. CB[7] derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems.


Assuntos
Alquinos/química , Sistemas de Liberação de Medicamentos , Imidazóis/química , Alquinos/metabolismo , Animais , Compostos Azo/química , Dióxido de Carbono/antagonistas & inibidores , Catálise , Bovinos , Cristalografia por Raios X , Dimerização , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Imidazóis/metabolismo , Isomerismo , Células MCF-7/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nanopartículas/química , Nanopartículas/uso terapêutico , Bloqueadores Neuromusculares/farmacocinética , Ratos , Termodinâmica , Testes de Toxicidade , Água/química
7.
J Am Chem Soc ; 135(6): 2198-206, 2013 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-23368960

RESUMO

Several small molecules and ions, notably carbon monoxide, cyanide, cyanate, and hydrogen sulfide, are potent inhibitors of Ni-containing carbon monoxide dehydrogenases (Ni-CODH) that catalyze very rapid, efficient redox interconversions of CO(2) and CO. Protein film electrochemistry, which probes the dependence of steady-state catalytic rate over a wide potential range, reveals how these inhibitors target particular oxidation levels of Ni-CODH relating to intermediates (C(ox), C(red1), and C(red2)) that have been established for the active site. The following properties are thus established: (1) CO suppresses CO(2) reduction (CO is a product inhibitor), but its binding affinity decreases as the potential becomes more negative. (2) Cyanide totally inhibits CO oxidation, but its effect on CO(2) reduction is limited to a narrow potential region (between -0.5 and -0.6 V), below which CO(2) reduction activity is restored. (3) Cyanate is a strong inhibitor of CO(2) reduction but inhibits CO oxidation only within a narrow potential range just above the CO(2)/CO thermodynamic potential--EPR spectra confirm that cyanate binds selectively to C(red2). (4) Hydrogen sulfide (H(2)S/HS(-)) inhibits CO oxidation but not CO(2) reduction--the complex on/off characteristics are consistent with it binding at the same oxidation level as C(ox) and forming a modified version of this inactive state rather than reacting directly with C(red1). The results provide a new perspective on the properties of different catalytic intermediates of Ni-CODH--uniting and clarifying many previous investigations.


Assuntos
Aldeído Oxirredutases/antagonistas & inibidores , Dióxido de Carbono/metabolismo , Monóxido de Carbono/farmacologia , Técnicas Eletroquímicas , Complexos Multienzimáticos/antagonistas & inibidores , Aldeído Oxirredutases/química , Aldeído Oxirredutases/metabolismo , Biocatálise , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/química , Monóxido de Carbono/antagonistas & inibidores , Monóxido de Carbono/química , Domínio Catalítico/efeitos dos fármacos , Cianetos/farmacologia , Sulfeto de Hidrogênio/farmacologia , Modelos Moleculares , Complexos Multienzimáticos/química , Complexos Multienzimáticos/metabolismo , Oxirredução , Relação Estrutura-Atividade
8.
Plant Cell Environ ; 34(1): 89-112, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21039609

RESUMO

Leaf respiration continues in the light but at a reduced rate. This inhibition is highly variable, and the mechanisms are poorly known, partly due to the lack of a formal model that can generate testable hypotheses. We derived an analytical model for non-photorespiratory CO2 release by solving steady-state supply/demand equations for ATP, NADH and NADPH, coupled to a widely used photosynthesis model. We used this model to evaluate causes for suppression of respiration by light. The model agrees with many observations, including highly variable suppression at saturating light, greater suppression in mature leaves, reduced assimilatory quotient (ratio of net CO2 and O2 exchange) concurrent with nitrate reduction and a Kok effect (discrete change in quantum yield at low light). The model predicts engagement of non-phosphorylating pathways at moderate to high light, or concurrent with processes that yield ATP and NADH, such as fatty acid or terpenoid synthesis. Suppression of respiration is governed largely by photosynthetic adenylate balance, although photorespiratory NADH may contribute at sub-saturating light. Key questions include the precise diel variation of anabolism and the ATP : 2e⁻ ratio for photophosphorylation. Our model can focus experimental research and is a step towards a fully process-based model of CO2 exchange.


Assuntos
Dióxido de Carbono/metabolismo , Escuridão , Luz , Modelos Teóricos , Folhas de Planta/metabolismo , Plantas/metabolismo , Trifosfato de Adenosina/metabolismo , Dióxido de Carbono/antagonistas & inibidores , Respiração Celular , Simulação por Computador , Elétrons , NAD/metabolismo , NADP/metabolismo , Consumo de Oxigênio , Fótons , Fotossíntese , Folhas de Planta/química , Plantas/química
9.
Neuroscience ; 175: 262-72, 2011 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-21130842

RESUMO

Compensated respiratory acidosis has been observed in a significant number of patients with active vestibular disease. We therefore hypothesized that the inner ear may play an unrecognized integral role in respiratory control. To test this premise, we investigated whether mice with induced inner ear injury demonstrated any alteration in their respiratory response to inhaled carbon dioxide (CO(2)). Experimental mice and control mice were included in two separate experiments. Intra-tympanic gentamycin injections were administered to induce inner ear damage in experimental animals. Hearing loss and vestibular dysfunction were tested 1-week after injections to confirm presence of inner ear insult, following which the animal's respiratory response to inhalation of 8% CO(2) was examined. Mice with inner ear injury (n=60) displayed a significantly diminished hypercapnic ventilatory response (HCVR). This contrasted with the normal HCVR seen in control mice that had not undergone tympanic injections (n=30), controls that received tympanic injections with saline (n=5), and controls that had gentamicin administered systemically (n=5). In response to inspired CO(2), the mean respiratory frequency of control mice increased by an average of 50% over their baseline values for both parts of the experiment. In contrast, the ear-damaged experimental group mean values increased by only three breaths per minute (bpm) (2%) in the first experiment and by 28 bpm (11%) in the second experiment. Inner ear damage significantly reduces the respiratory response to CO(2) inhalation. In addition to the established role of the inner ear organ in hearing and balance, this alludes to an unidentified function of the inner ear and its interconnecting neuronal pathways in respiratory regulation. This finding may offer valuable new clues for disease states with abnormal respiratory control where inner ear dysfunction may be present.


Assuntos
Acidose Respiratória/fisiopatologia , Dióxido de Carbono/fisiologia , Hipercapnia/fisiopatologia , Mecânica Respiratória/fisiologia , Doenças Vestibulares/fisiopatologia , Vestíbulo do Labirinto/fisiopatologia , Acidose Respiratória/etiologia , Animais , Dióxido de Carbono/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Hipercapnia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos CBA , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Mecânica Respiratória/efeitos dos fármacos , Taxa Respiratória/efeitos dos fármacos , Taxa Respiratória/fisiologia , Doenças Vestibulares/complicações , Vestíbulo do Labirinto/efeitos dos fármacos , Vestíbulo do Labirinto/lesões
10.
Respir Res ; 11: 117, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20796307

RESUMO

BACKGROUND: Prolonged weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications.There is evidence in patients around the period of extubation that helium-oxygen leads to a reduction in the work of breathing. Therefore breathing helium-oxygen during weaning may be a useful adjunct to facilitate weaning. We hypothesised that breathing helium-oxygen would reduce carbon dioxide production during the weaning phase of mechanical ventilation. MATERIALS/PATIENTS AND METHODS: We performed a prospective randomised controlled single blinded cross-over trial on 19 adult intensive care patients without significant airways disease who fulfilled criteria for weaning with CPAP. Patients were randomised to helium-oxygen and air-oxygen delivered during a 2 hour period of CPAP ventilation. Carbon dioxide production (VCO2) was measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph. RESULTS: Compared to air-oxygen, helium-oxygen significantly decreased VCO2 production at the end of the 2 hour period of CPAP ventilation; there was a mean difference in CO2 production of 48.9 ml/min (95% CI 18.7-79.2 p = 0.003) between the groups. There were no significant differences in other respiratory and haemodynamic parameters. CONCLUSION: This study shows that breathing a helium-oxygen mixture during weaning reduces carbon dioxide production. This physiological study supports the need for a clinical trial of helium-oxygen mixture during the weaning phase of mechanical ventilation with duration of weaning as the primary outcome. TRIAL REGISTRATION: ISRCTN56470948.


Assuntos
Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/metabolismo , Hélio/administração & dosagem , Oxigênio/administração & dosagem , Desmame do Respirador/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Respiração Artificial/métodos , Método Simples-Cego , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-17258917

RESUMO

Oxygen binding to hemoglobin (Hb) depends on allosteric effectors (CO(2), lactate and protons) that may increase drastically in concentration during exercise. The effectors share common binding sites on the Hb molecules, predicting mutual interaction in their effects on Hb (de)oxygenation. We analysed the effects of lactate and CO(2), separately and in combination, on O(2) binding of purified human Hb at 37 degrees C and physiological pH and chloride values. We demonstrate pH-dependent, inhibitory interactions between lactate binding and CO(2) binding (carbamate formation); at pH 7.4, physiological CO(2) tension ( approximately 43 mm Hg) reduced lactate binding more markedly ( approximately 75%), than lactate (50 mM) inhibited carbamate formation ( approximately 25%). In contrast to previous studies on blood and Hb solutions, we moreover find that added lactate neither 'reverses' oxylabile carbamate formation (resulting in lower carbamate levels in deoxyHb than in oxyHb) nor exerts greater allosteric effects on Hb-O(2) affinity than equal increases in chloride ion concentrations.


Assuntos
Dióxido de Carbono/metabolismo , Hemoglobinas/metabolismo , Ácido Láctico/metabolismo , Oxigênio/química , Regulação Alostérica , Sítios de Ligação , Carbamatos/metabolismo , Dióxido de Carbono/antagonistas & inibidores , Feminino , Hemoglobinas/química , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/antagonistas & inibidores
12.
Chem Senses ; 29(4): 351-61, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15150148

RESUMO

Inhibitory responses of slowly adapting pulmonary stretch receptor (SAR) activity to CO(2) inhalation (maximal tracheal CO(2) concentration ranging from 9.5 to 12.5%) for approximately 60 s were examined before and after administration of acetazolamide (a carbonic anhydrase inhibitor) or 4-aminopyridine (4-AP, a K(+) channel blocker). The experiments were performed in 35 anesthetized, artificially ventilated rats after unilateral vagotomy. Sixty-eight of eighty-four SARs were inhibited by CO(2) inhalation. The SAR inhibition was attenuated by pretreatment with either acetazolamide (20 mg/kg, n = 10) or 4-AP (0.7 and 2.0 mg/kg, n = 10). In other series of experiments, stainings to show the existence of carbonic anhydrase (CA) enzymatic reaction were not found in the smooth muscle of either extrapulmonary or intrapulmonary bronchi. Protein gene product 9.5 (PGP 9.5)-immunoreactive SAR terminals to form leaflike extensions were found in the bronchioles at different diameters and were smooth-muscle-related receptors. But in the same sections, CA isozyme II-like (erythrocyte CA) immunoreactive SAR terminals were not identified. These results suggest that CO(2)-induced inhibition of SARs may be involved in the CA-dependent CO(2) hydration in addition to the activation of 4-AP sensitive K(+) currents.


Assuntos
4-Aminopiridina/farmacologia , Acetazolamida/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Receptores Pulmonares de Alongamento/fisiologia , Administração por Inalação , Animais , Dióxido de Carbono/administração & dosagem , Anidrase Carbônica II/fisiologia , Miócitos de Músculo Liso/citologia , Ratos , Traqueia/citologia
13.
Am J Physiol Renal Physiol ; 285(5): F930-7, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12851254

RESUMO

In rat outer medullary collecting duct (OMCD), the mechanism(s) and regulation of H+ secretion are not understood fully. The effect of changes in acid-base balance and the renin-angiotensin system on net H+ secretion was explored. Rats received NaCl, NaHCO3, NH4Cl, or nothing in their drinking water for 7 days. Total ammonia and total CO2 (JtCO2) fluxes were measured in OMCD tubules perfused in vitro from rats in each treatment group. JtCO2 was reduced in tubules from rats drinking NH4Cl relative to those drinking NaHCO3. Because NH4Cl intake increases plasma renin and aldosterone, we asked if upregulation of the renin-angiotensin system reduces net H+ secretion. Deoxycorticosterone pivalate administered in vivo did not affect JtCO2. However, ANG II given in vivo at 0.1 ng/min reduced JtCO2 by 35%. To determine if ANG II has a direct effect on acid secretion, JtCO2 was measured with ANG II applied in vitro. ANG II (10-8 M) present in the bath solution reduced JtCO2 by 35%. This ANG II effect was not observed in the presence of the AT1 receptor blocker candesartan. In conclusion, in rat OMCD, JtCO2 is paradoxically reduced with NH4Cl ingestion. Increased circulating ANG II, as occurs during metabolic acidosis, reduces JtCO2.


Assuntos
Ácidos/metabolismo , Angiotensina II/farmacologia , Medula Renal , Túbulos Renais Coletores/metabolismo , Acidose/metabolismo , Aldosterona/farmacologia , Alcalose/metabolismo , Amônia/metabolismo , Amônia/urina , Cloreto de Amônio/farmacologia , Animais , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/metabolismo , Sinergismo Farmacológico , Técnicas In Vitro , Ratos , Ratos Sprague-Dawley
14.
FEBS Lett ; 542(1-3): 42-6, 2003 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-12729895

RESUMO

The CO(2)-regulatory function of the AT-rich element in the promoter for ribulose-1,5-bisphosphate carboxylase/oxygenase (rbc) genes in the cyanobacterium Synechococcus sp. PCC7002 was analyzed using the transcription factor decoy approach. Double-stranded phosphorothioate AT-rich oligonucleotides with high affinity for a sequence-specific DNA-binding protein were successfully introduced into cyanobacterial cells in culture without any transfection reagent. The AT-rich decoy oligonucleotides interfered with CO(2) regulation of rbc expression by blocking the binding of the sequence-specific DNA-binding protein, indicating that the AT-rich element plays a critical role in CO(2) regulation for rbc genes. The decoy oligonucleotide approach to cyanobacteria provides a simple and excellent tool for investigating transcriptional regulation in vivo.


Assuntos
Dióxido de Carbono/antagonistas & inibidores , Cianobactérias/enzimologia , Regulação Bacteriana da Expressão Gênica , Oligonucleotídeos/farmacologia , Ribulose-Bifosfato Carboxilase/genética , Sequência Rica em At , Transporte Biológico , Cianobactérias/efeitos dos fármacos , Cianobactérias/genética , Proteínas de Ligação a DNA/metabolismo , Repressão Enzimática , Fluoresceína-5-Isotiocianato , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Regiões Promotoras Genéticas , Elementos de Resposta , Ativação Transcricional/efeitos dos fármacos
15.
J Neurosci Res ; 65(5): 403-7, 2001 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-11536323

RESUMO

In the present study, we investigated effects of estrogen on cell death induced by carboxy-terminal fragment of amyloid precursor protein (CT), a candidate causative substance in the pathogenesis of Alzheimer's disease. 17 beta-Estradiol attenuated CT-induced cell death in PC12 cells, whereas 17 alpha-estradiol, nonestrogenic stereoisomer, did not exert any significant protective effect on CT-induced cell death. These results suggest that protective effects of estrogen may be mediated by estrogen receptor (ER) in PC12 cells. To confirm the results, we determined the effects of tamoxifen, an estrogen receptor antagonist. Tamoxifen blocked the protective effects of 17 beta-estradiol, although it did not affect those of 17 alpha-estradiol. Overall, it might be thought that the protective effect of estradiol on CT-induced cell death is achieved by hormonal properties mediated through the estrogen receptor rather than the structural properties as a reducing agent.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Dióxido de Carbono/toxicidade , Morte Celular/efeitos dos fármacos , Estradiol/farmacologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Receptores Estrogênicos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Dióxido de Carbono/antagonistas & inibidores , Morte Celular/fisiologia , Antagonistas de Estrogênios/farmacologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Células PC12/efeitos dos fármacos , Células PC12/metabolismo , Células PC12/patologia , Fragmentos de Peptídeos/antagonistas & inibidores , Estrutura Terciária de Proteína/efeitos dos fármacos , Estrutura Terciária de Proteína/fisiologia , Ratos , Receptores Estrogênicos/efeitos dos fármacos , Tamoxifeno/farmacologia
16.
Trends Cardiovasc Med ; 9(1-2): 49-54, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10189967

RESUMO

A mild elevation in serum homocysteine levels is an independent risk factor for arteriosclerosis and venous thrombosis. Despite the clinical significance of homocysteine, however, the molecular mechanisms of homocysteine-induced arteriosclerosis have not been completely elucidated. This lack of understanding is due in large part to the excessively high concentrations of homocysteine (greater than 1 mM) used in experiments. Many of homocysteine's effects have been attributed to its prooxidant activity, which is implicated as the mechanism through which it inhibits production of endothelium-derived relaxing factor and activates quiescent vascular smooth muscle cells. We have found that homocysteine at 10 to 50 microM (but not cysteine) inhibits progression of the vascular endothelial cell cycle at or before the G1-S junction. This inhibition appears to be mediated by decreases in the carboxyl methylation, membrane association, and activity of p21ras--a major G1 regulator. Homocysteine may play an important role in promoting arteriosclerosis by inducing endothelial dysfunction, by inhibiting endothelial cell regeneration, and by directly activating quiescent vascular smooth muscle cells.


Assuntos
Homocisteína/metabolismo , Doenças Vasculares/etiologia , Arteriosclerose/etiologia , Dióxido de Carbono/antagonistas & inibidores , Membrana Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Radicais Livres/antagonistas & inibidores , Fase G1/efeitos dos fármacos , Homocisteína/sangue , Homocisteína/farmacologia , Humanos , Metilação , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Oxidantes/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Fatores de Risco , Fase S/efeitos dos fármacos , Trombose Venosa/etiologia
17.
Invest Ophthalmol Vis Sci ; 38(3): 652-7, 1997 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-9071219

RESUMO

PURPOSE: To determine whether angiotensin II (Ang II), a vasoconstrictive peptide, changes the relaxation effect of elevated partial pressure of carbon dioxide (PCO2) on pericytes. METHODS: The contractile tone of cultured bovine retinal pericytes was measured when the ambient PCO2 was elevated in the absence or the presence of Ang II. All experiments were performed in the bicarbonate-buffered solution at 37 degrees C. RESULTS: Ang II (10(-6) M) by itself did not increase the baseline tone of the pericytes. Raising the PCO2 from 5% to 20% acidified the solution (pH dropped 0.51 +/- 0.02 U) and caused a sustained and statistically significant 22.9% +/- 4.6% relaxation of pericytes within 5 minutes (n = 8). In the presence of Ang II (10(-6) M), the maximum relaxation induced by 20% PCO2 was only 12.6% +/- 4.5% (n = 6) at 3 minutes, and the relaxation was not sustained. The effect of Ang II was statistically significant. Pretreatment with the competitive Ang II receptor antagonist saralasin (10(-6) M) for 10 minutes completely abolished the effect of Ang II (10(-6) M) on the response of pericytes to 20% PCO2. Saralasin by itself had no effect. CONCLUSIONS: Ang II attenuated the relaxing response of pericytes to elevated PCO2 through saralasin-sensitive Ang II receptors. Results suggest that some vasoactive agents, such as Ang II, could affect the pericyte responses to metabolic needs as signaled by local PCO2. This experimental design may permit further investigation of the altered physiology of local blood flow regulation.


Assuntos
Angiotensina II/farmacologia , Capilares/citologia , Dióxido de Carbono/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Vasos Retinianos/fisiologia , Vasoconstritores/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Capilares/efeitos dos fármacos , Capilares/fisiologia , Dióxido de Carbono/farmacologia , Bovinos , Células Cultivadas , Concentração de Íons de Hidrogênio , Receptores de Angiotensina/metabolismo , Vasos Retinianos/citologia , Vasos Retinianos/efeitos dos fármacos , Saralasina/farmacologia
18.
J Gastroenterol Hepatol ; 12(9-10): 678-84, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9407333

RESUMO

Ulcerative colitis is associated with a selective reduction of n-butyrate oxidation by the colonic epithelial cells although the reason for this has been unclear. Colonic epithelial cell n-butyrate oxidation can be inhibited in vitro by incubation with sulphide but the role of mucosal detoxification of sulphide in the metabolic welfare of the colonic mucosa has not been examined. This study aimed to assess the role mucosal detoxification of sulphide by thiolmethyltransferase (TMT)-mediated methylation may play in protecting the healthy colonic mucosa from the adverse effects of luminal sulphide. Colonic epithelial cell suspensions from healthy human proximal (n = 9) and distal colon (n = 10) were incubated in the presence of 14C-labelled n-butyrate (5 mmol/L) alone, butyrate plus sodium hydrogen sulphide (NaHS) (1.5 mmol/L), or butyrate plus NaHS plus S-adenosyl-methionine 1,4 butane disulphonate (SAMe) (5 mmol/L). Study end points were metabolic performance (14CO2 production) and mucosal TMT activity. Incubation with NaHS induced a significant inhibition of 14CO2 production compared with control incubations (P < 0.001) which was similar for proximal and distal colonic cell suspensions. S-adenosyl-methionine 1,4 butane disulphonate reversed this effect completely in proximal but not in distal cell incubations, suggesting a greater susceptibility of the distal colon to the sulphide effect. Although median whole mucosal TMT values did not differ between proximal and distal colonic mucosa, a non-normal distribution of distal TMT values was observed. However, neither the degree of sulphide inhibition of control 14CO2 production nor the degree to which SAMe reversed this inhibition correlated with whole mucosal TMT activity. The study concluded that regional variation exists in TMT activity in the human colon but whilst methylation appears to protect colonic epithelial cells against sulphide-induced inhibition of n-butyrate oxidation, this cannot be directly correlated with mucosal TMT activity.


Assuntos
Colo/metabolismo , Mucosa Intestinal/metabolismo , Metiltransferases/metabolismo , Idoso , Butiratos/farmacologia , Ácido Butírico , Dióxido de Carbono/antagonistas & inibidores , Dióxido de Carbono/metabolismo , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/enzimologia , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , S-Adenosilmetionina/farmacologia , Sulfetos/farmacologia
19.
Anesthesiology ; 80(6): 1303-10, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8010477

RESUMO

BACKGROUND: It has been reported that physostigmine antagonizes morphine-induced respiratory depression, but it is not known whether this is due to a central chemoreceptor effect, an effect on the peripheral chemoreflex loop, or both. We therefore assessed the effect of morphine and physostigmine on the normoxic hypercapnic ventilatory response mediated by the central and peripheral chemoreceptors in ten alpha-chloralose-urethan-anesthetized cats. METHODS: The breath-by-breath ventilatory responses to stepwise changes in end-tidal CO2 tension were determined before (control), after administration of morphine hydrochloride (0.15 mg.kg-1) and during intravenous infusion of physostigmine salicylate (bolus of 0.05 mg.kg-1 followed by 0.025 mg.kg-1.h-1). Each response was separated into a central and a peripheral chemoreflex characterized by CO2 sensitivity (Sc and Sp), time constant, time delay, and apneic threshold (a single off-set B). RESULTS: Morphine increased B and decreased Sc and Sp (P < 0.01), but not the ratio Sp/Sc. Subsequent infusion of physostigmine decreased B (P < 0.01), without further change of Sp and Sc. Premedication with physostigmine decreased B, Sp and Sc (P < 0.01) vs. control, but not Sp/Sc. Subsequent administration of morphine decreased Sp and Sc further but increased B (P < 0.01), while Sp/Sc remained constant. CONCLUSIONS: Because morphine diminishes the Sc and Sp of the chemoreflex loop to the same extent this depressant effect is presumably due to an action on the respiratory integrating centers rather than on the peripheral and central chemoreceptors as such and is not antagonized by physostigmine. We argue that the increase in B may be due to changes in the amount of acetylcholine available in the brain and can be antagonized by physostigmine.


Assuntos
Anestesia , Dióxido de Carbono/antagonistas & inibidores , Células Quimiorreceptoras/efeitos dos fármacos , Morfina/farmacologia , Fisostigmina/farmacologia , Respiração/efeitos dos fármacos , Animais , Dióxido de Carbono/farmacologia , Gatos , Feminino , Masculino , Naloxona/farmacologia
20.
Brain Res ; 612(1-2): 122-9, 1993 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-8330192

RESUMO

The goal of this study was to examine the role of the enzyme, carbonic anhydrase, in oral trigeminal chemoreception with particular regard to the reception of CO2. Using both single and multiunit recordings of trigeminal neurons in the lingual nerve of rat, we measured responses to cool (24 degrees C), noxiously hot (55 degrees C) and cold (8 degrees C) H2O, NH4Cl and supersaturated solutions of CO2 (24 degrees C and 33 degrees C). The importance of peripheral carbonic anhydrase was tested by inhibiting enzyme activity with acetazolamide (15 mg/kg b.w.). Single unit responses to CO2 and HCl suggest that neural sensitivity to CO2 is not simply a function of extraepithelial pH. Responses to CO2 were significantly inhibited by acetazolamide while the responses to thermal stimuli and NH4Cl were not. The results support a role for carbonic anhydrase in trigeminal responses to CO2. Furthermore, the results suggest that intraepithelial acidification mediated by carbonic anhydrase may be the basis for sensitivity to CO2.


Assuntos
Acetazolamida/farmacologia , Dióxido de Carbono/antagonistas & inibidores , Língua/inervação , Nervo Trigêmeo/efeitos dos fármacos , Cloreto de Amônio/farmacologia , Animais , Dióxido de Carbono/farmacologia , Anidrases Carbônicas/metabolismo , Células Quimiorreceptoras/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Temperatura , Língua/efeitos dos fármacos
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