RESUMO
Cardiac pressor agents typically reduce the amount of blood pumped with each heartbeat. Cardiovascular hemodynamic principles can show whether such a response is physiologic or maladaptive.
Assuntos
Fármacos Cardiovasculares/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Receptores de Superfície Celular/agonistas , Hemodinâmica/efeitos dos fármacos , Humanos , Receptores de Superfície Celular/metabolismoRESUMO
Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of biological functions. Details of its biochemistry, however, remain poorly understood. The broader chemistry of nitrogen monoxide (NO) involves a redox array of species with distinctive properties and reactivities: NO+ (nitrosonium), NO., and NO- (nitroxyl anion). The integration of this chemistry with current perspectives of NO biology illuminates many aspects of NO biochemistry, including the enzymatic mechanism of synthesis, the mode of transport and targeting in biological systems, the means by which its toxicity is mitigated, and the function-regulating interaction with target proteins.
Assuntos
Óxido Nítrico/metabolismo , Aminoácido Oxirredutases/metabolismo , Animais , Arginina/metabolismo , Humanos , Óxido Nítrico/química , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase , OxirreduçãoRESUMO
Several ion channels are reportedly redox responsive, but the molecular basis for the changes in activity is not known. The mechanism of nitric oxide action on the cardiac calcium release channel (ryanodine receptor) (CRC) in canines was explored. This tetrameric channel contains approximately 84 free thiols and is S-nitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per CRC subunit) led to progressive channel activation that was reversed by denitrosylation. In contrast, oxidation of 20 to 24 thiols per CRC (5 or 6 per subunit) had no effect on channel function. Oxidation of additional thiols (or of another class of thiols) produced irreversible activation. The CRC thus appears to be regulated by poly-S-nitrosylation (multiple covalent attachments), whereas oxidation can lead to loss of control. These results reveal that ion channels can differentiate nitrosative from oxidative signals and indicate that the CRC is regulated by posttranslational chemical modification(s) of sulfurs.
Assuntos
Cálcio/metabolismo , Mercaptoetanol , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Compostos Nitrosos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , S-Nitrosotióis , Animais , GMP Cíclico/metabolismo , Cisteína/análogos & derivados , Cisteína/farmacologia , Ditiotreitol/farmacologia , Cães , Condutividade Elétrica , Etilmaleimida/farmacologia , Glutationa/análogos & derivados , Glutationa/farmacologia , Lipossomos/metabolismo , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Nitrosação , Compostos Nitrosos/farmacologia , Oxirredução , Proteolipídeos/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , S-Nitrosoglutationa , Compostos de Sulfidrila/metabolismoRESUMO
The binding of oxygen to heme irons in hemoglobin promotes the binding of nitric oxide (NO) to cysteinebeta93, forming S-nitrosohemoglobin. Deoxygenation is accompanied by an allosteric transition in S-nitrosohemoglobin [from the R (oxygenated) to the T (deoxygenated) structure] that releases the NO group. S-nitrosohemoglobin contracts blood vessels and decreases cerebral perfusion in the R structure and relaxes vessels to improve blood flow in the T structure. By thus sensing the physiological oxygen gradient in tissues, hemoglobin exploits conformation-associated changes in the position of cysteinebeta93 SNO to bring local blood flow into line with oxygen requirements.
Assuntos
Circulação Cerebrovascular , Hemodinâmica , Hemoglobinas/fisiologia , Mercaptoetanol , Oxigênio/sangue , S-Nitrosotióis , Animais , Pressão Sanguínea , Cisteína/química , Cisteína/metabolismo , Hemoglobinas/análise , Hemoglobinas/química , Modelos Moleculares , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Compostos Nitrosos/sangue , Oxiemoglobinas/química , Conformação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
Only a few intracellular S-nitrosylated proteins have been identified, and it is unknown if protein S-nitrosylation/denitrosylation is a component of signal transduction cascades. Caspase-3 zymogens were found to be S-nitrosylated on their catalytic-site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway. Decreased caspase-3 S-nitrosylation was associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active-site thiol. Protein S-nitrosylation/denitrosylation can thus serve as a regulatory process in signal transduction pathways.
Assuntos
Caspases/metabolismo , Cisteína/metabolismo , Mercaptoetanol , Óxido Nítrico/metabolismo , S-Nitrosotióis , Receptor fas/fisiologia , Animais , Apoptose , Sítios de Ligação , Caspase 3 , Linhagem Celular , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Precursores Enzimáticos/metabolismo , Humanos , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/metabolismo , Compostos Nitrosos/metabolismo , Transdução de Sinais , ômega-N-Metilarginina/farmacologiaRESUMO
Recent evidence indicates that the NO-related species, nitroxyl anion (NO), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO- -unlike NO*, but reminiscent of NO+ transfer (or S-nitrosylation)- -reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.
Assuntos
Neurotoxinas/metabolismo , Óxidos de Nitrogênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Ânions/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Feminino , N-Metilaspartato/farmacologia , Neurônios/metabolismo , Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/metabolismo , Oócitos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Compostos de Sulfidrila/química , Compostos de Sulfidrila/metabolismo , Xenopus laevisRESUMO
Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.
Assuntos
Plaquetas/fisiologia , Endotélio Vascular/fisiologia , Homocisteína/farmacologia , Óxido Nítrico/fisiologia , Óxidos de Nitrogênio/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Animais , Aorta , Plaquetas/efeitos dos fármacos , Bovinos , Células Cultivadas , Colágeno/farmacologia , Cobre/farmacologia , GMP Cíclico/sangue , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Homocisteína/antagonistas & inibidores , Homocistina/farmacologia , Humanos , Peróxido de Hidrogênio/metabolismo , Técnicas In Vitro , Ferro/farmacologia , Cinética , Medições Luminescentes , Espectroscopia de Ressonância Magnética , Modelos Cardiovasculares , Óxido Nítrico/farmacologiaRESUMO
Plasma albumin reacts with nitric oxide (NO) to form the bioactive adduct, S-nitroso-albumin (S-NO-albumin). The limited intracellular access of S-NO-albumin suggests the need for a vascular transfer mechanism of NO from a large plasma S-NO-albumin pool to effect biologic function. To study the role of low molecular weight (LMW) thiols in NO transfer in vivo, we administered intravenous S-NO-albumin (1-300 nmol/kg) to rabbits before and after an intravenous infusion of L-cysteine or N-acetyl-L-cysteine. S-NO-albumin produced dose-dependent hypotension that was significantly augmented by prior infusion of either LMW thiol. LMW thiol infusion significantly accelerated the rate of onset and reduced the duration of action of the hypotension induced by S-NO-albumin. The hemodynamic effects of S-NO-albumin after pretreatment with LMW thiols were mimicked by administration of the corresponding LMW S-nitrosothiol. The transfer of NO from albumin to L-cysteine was directly measured in rabbit plasma using a novel technique that couples high performance liquid chromatography to electrochemical detection. These data demonstrate that NO exchange between plasma protein thiol-bound NO and available LMW thiol pools (transnitrosation) occurs in vivo.
Assuntos
Mercaptoetanol , Óxido Nítrico/metabolismo , Compostos Nitrosos/sangue , Compostos Nitrosos/metabolismo , S-Nitrosotióis , Soroalbumina Bovina/metabolismo , Compostos de Sulfidrila/metabolismo , Acetilcisteína/administração & dosagem , Acetilcisteína/análogos & derivados , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Animais , Transporte Biológico , Pressão Sanguínea/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Cisteína/administração & dosagem , Cisteína/análogos & derivados , Cisteína/sangue , Cisteína/metabolismo , Cisteína/farmacologia , Nitrosação , Compostos Nitrosos/administração & dosagem , Compostos Nitrosos/farmacologia , Ligação Proteica , Coelhos , Compostos de Sulfidrila/sangue , Resistência Vascular/efeitos dos fármacosRESUMO
Nitric oxide (NO) is an inhibitor of gastrointestinal smooth muscle. Model systems of the gut predict the NO will complex with biological thiol (SH) groups, yielding S-nitrosothiols (RS-NO), which may limit the propensity to form mutagenic nitrosamines. The inhibitory effects of NO and its biologically relevant adducts on sphincter of Oddi (SO) motility have been inferred from animal studies; however, their importance in regulating human SO is not known. The objectives of this study were to (a) provide histologic confirmation of nitric oxide synthase (NOS) in human SO; (b) characterize the pharmacology of S-nitroso-N-acetylcysteine (SNAC), an exemplary S-nitrosothiol, on SO motility in a rabbit model; and (c) study the effects of topical SNAC on SO motility in humans. Immunocytochemical and histochemical identification of NOS was performed in human SO. The pharmacologic response of SNAC was defined in isolated rabbit SO using a standard bioassay. Topical SNAC was then applied to the duodenal papilla in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) and biliary manometry. NOS was localized to nerve fibers and bundles of the SO in rabbits and humans. SNAC inhibited spontaneous motility (frequency and amplitude) as well as acetylcholine-induced elevations in SO basal pressure in the rabbit model. In patients undergoing ERCP and biliary manometry, topical SNAC inhibited SO contraction freqency, basal pressure, and duodenal motility. NOS is localized to neural elements in human SO, implicating a role for NO in regulating SO function. Supporting this concept, SNAC is an inhibitor of SO and duodenal motility when applied topically to humans during ERCP. Our data suggest a novel clinical approach using local NO donors to control gastrointestinal motility and regulate sphincteric function.
Assuntos
Acetilcisteína/análogos & derivados , Óxido Nítrico/fisiologia , Esfíncter da Ampola Hepatopancreática/efeitos dos fármacos , Acetilcisteína/farmacologia , Aminoácido Oxirredutases/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Óxido Nítrico Sintase , Coelhos , Esfíncter da Ampola Hepatopancreática/fisiologiaRESUMO
Recent evidence suggests that sulfhydryl species can react with oxides of nitrogen under physiologic conditions and thereby stabilize endothelium-derived relaxing factor (EDRF) activity, but the presence of a specific in vivo thiol carrier for nitric oxide (NO) remains controversial. The single free sulfhydryl of serum albumin is the most abundant thiol species in plasma (approximately 0.5 mM) and is particularly reactive towards NO. To examine the potential role of serum albumin in endogenous nitric oxide metabolism, we synthesized S-nitroso-BSA (S-NO-BSA), a model S-nitroso-protein, and examined its effects on platelet function and coronary and systemic vascular tone in 16 mongrel dogs. Intravenous bolus S-NO-BSA markedly reduced mean arterial pressure in a dose-dependent manner and proved seven and a half-fold less potent than intravenous nitroglycerin and 10-fold less potent than intravenous S-nitroso-cysteine (half-maximal response of 75 nmol/kg compared to 10 and 7.5 nmol/kg, respectively; P < 0.05); when given by intravenous infusion (half-maximal response = 10 nmol/kg per min), however, S-NO-BSA and nitroglycerin were equipotent. Intravenous bolus S-NO-BSA had a greater duration of action than either nitroglycerin or S-nitroso-cysteine and produced marked prolongation of the template bleeding time associated with dose-dependent inhibition of ex vivo platelet aggregation (half-maximal response approximately 70 nmol/kg). Intracoronary S-NO-BSA increased coronary blood flow (mean +/- SEM) less effectively than nitroprusside, acetylcholine, or S-nitroso-cysteine (165% +/- 24% vs. 315% +/- 82%, 483% +/- 55%, or 475% +/- 66%, respectively; P < 0.05) although with much longer duration of action. On a molar basis, S-nitroso-cysteine proved more effective than S-nitroso-BSA, nitroprusside, or acetylcholine as an epicardial coronary vasodilator. Thus, serum albumin reacts with oxides of nitrogen to form a stable S-nitroso-thiol with properties reminiscent of authentic EDRF supporting the view that protein associated thiol may participate in the action and metabolism of EDRF.
Assuntos
Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , S-Nitrosotióis , Soroalbumina Bovina/metabolismo , Acetilcolina/farmacologia , Animais , Tempo de Sangramento , Plaquetas/fisiologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Cisteína/análogos & derivados , Cisteína/farmacologia , Cães , Feminino , Meia-Vida , Masculino , Relaxamento Muscular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico/farmacologia , Nitroglicerina/farmacologia , Nitroprussiato/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Soroalbumina Bovina/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND: We have previously shown that mixing the S-nitrosylating agent ethyl nitrite with carbon dioxide can attenuate pneumoperitoneum-induced decreases in splanchnic blood flow, but it was unclear if this agent would alter gastric function. This question was answered using rats by assessing gastric emptying and gastrointestinal transit times following gavage with radioactive chromium. METHODS: There were five experimental groups: absolute control, anesthesia control, and carbon dioxide alone or with 100 or 300 parts per million ethyl nitrite. The period of insufflation was 1 h, and all animals were euthanized 6.5 h after chromium administration. RESULTS: The mean amount of radioactivity remaining in the stomach ranged between 16% and 27% of the total administered; these differences were not statistically significant (p > 0.05). Modest differences in chromium distribution were identified in the gastrointestinal tract, but for all treatments, the peak amount of radioactivity was located in the distal portion. Location of the peak, expressed as a percentage of total tract length, varied between 70% and 85% (p = 0.366). CONCLUSIONS: This study found no adverse effect of ethyl nitrite on postoperative gastric emptying or gastrointestinal transit time following pneumoperitoneum. The findings support continued assessment of the clinical utility of ethyl nitrite in the setting of laparoscopic surgery.
Assuntos
Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Nitritos/farmacologia , Pneumoperitônio Artificial , Animais , Dióxido de Carbono/farmacologia , Radioisótopos de Cromo , Gases , Masculino , Ratos , Ratos Sprague-DawleyAssuntos
Mercaptoetanol , Óxido Nítrico/metabolismo , Compostos Nitrosos/química , Compostos Nitrosos/metabolismo , S-Nitrosotióis , Motivos de Aminoácidos , Animais , Biotinilação , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Conformação Proteica , Canal de Liberação de Cálcio do Receptor de Rianodina/químicaRESUMO
Nitric oxide (NO) or related molecules of both endogenous and exogenous origin inhibit programmed cell death in a variety of cells and tissues. This general protective function is largely independent of the apoptotic stimulus. S-nitrosylation of the catalytic-site cysteine of caspases is a well-established and possibly widespread mechanism of enzyme inhibition that protects from cell death. However, NO may inhibit apoptosis by additional mechanisms. The physiological and pathological significance of NO's anti-apoptotic activity remains to be determined in most cases.
Assuntos
Morte Celular/fisiologia , Citoproteção/fisiologia , Óxido Nítrico/química , Óxido Nítrico/fisiologia , Animais , HumanosRESUMO
The effects of NO-related activity and cellular thiol redox state on basal L-type calcium current, ICa,L, in ferret right ventricular myocytes were studied using the patch clamp technique. SIN-1, which generates both NO. and O2-, either inhibited or stimulated ICa,L. In the presence of superoxide dismutase only inhibition was seen. 8-Br-cGMP also inhibited ICa,L, suggesting that the NO inhibition is cGMP-dependent. On the other hand, S-nitrosothiols (RSNOs), which donate NO+, stimulated ICa,L. RSNO effects were not dependent upon cell permeability, modulation of SR Ca2+ release, activation of kinases, inhibition of phosphatases, or alterations in cGMP levels. Similar activation of ICa,L by thiol oxidants, and reversal by thiol reductants, identifies an allosteric thiol-containing "redox switch" on the L-type calcium channel subunit complex by which NO/O2- and NO+ transfer can exert effects opposite to those produced by NO. In sum, our results suggest that: (a) both indirect (cGMP-dependent) and direct (S-nitrosylation/oxidation) regulation of ventricular ICa,L, and (b) sarcolemma thiol redox state may be an important determinant of ICa,L activity.
Assuntos
Canais de Cálcio/metabolismo , Miocárdio/metabolismo , Animais , Canais de Cálcio/efeitos dos fármacos , Espaço Extracelular/metabolismo , Furões , Ventrículos do Coração , Masculino , Molsidomina/análogos & derivados , Molsidomina/farmacologia , Miocárdio/citologia , Óxido Nítrico/fisiologia , Compostos Nitrosos/metabolismo , Oxirredução , Técnicas de Patch-Clamp , Compostos de Sulfidrila/fisiologiaRESUMO
Organic nitrates, cornerstones of antianginal therapy, are believed to exert their principal anti-ischemic benefit by relaxing vascular smooth muscle. Recent evidence suggests that these compounds and related nitro(so) vasodilators are also potent platelet inhibitors. In view of the well recognized role of thrombotic events mediated by platelets in acute coronary syndromes, the antiplatelet effect of nitrates may also be of mechanistic importance in the treatment of these disorders. This review details the biochemical mechanism by which nitro(so) compounds inhibit platelet function and summarizes the in vitro and in vivo evidence that supports their antithrombotic effects.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Nitratos/farmacologia , Compostos Nitrosos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Angina Instável/tratamento farmacológico , Humanos , Infarto do Miocárdio/tratamento farmacológico , Nitratos/uso terapêutico , Nitroprussiato/farmacologia , Nitroprussiato/uso terapêutico , Compostos Nitrosos/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Terapia TrombolíticaRESUMO
OBJECTIVES: This investigation sought to determine whether endothelium-derived nitric oxide contributes to hypoxia-induced systemic vasodilation and pulmonary vasoconstriction in humans. BACKGROUND: Endothelium-derived nitric oxide contributes to basal systemic and pulmonary vascular resistance. During hypoxia, systemic vasodilation and pulmonary vasoconstriction occur. There are some data indicating that endothelium-derived nitric oxide mediates changes in vascular resistance during hypoxia, but much of it is contradictory, and none has been derived from normal humans. METHODS: The hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, were studied in healthy volunteers under normoxic and hypoxic conditions. A Swan-Ganz catheter and radial artery cannula were inserted to measure right atrial, pulmonary artery, pulmonary capillary wedge and systemic blood pressures. Cardiac output was measured by thermodilution. Systemic vascular resistance and pulmonary vascular resistance were calculated. The pharmacokinetics of L-NMMA (300 mg intravenously) was studied during normoxia in six subjects. Hypoxia was induced in eight subjects who inspired a mixture of nitrogen and oxygen through a gas blender adjusted to reduce the partial pressure of oxygen from (mean +/- SE) 98 +/- 4 to 48 +/- 1 mm Hg. RESULTS: During normoxia, L-NMMA increased systemic vascular resistance from 1,108 +/- 74 to 1,705 +/- 87 dynes-s-cm-5 and increased pulmonary vascular resistance from 60 +/- 5 to 115 +/- 9 dynes-s-cm-5 (p < or = 0.01 for each). Peak effects occurred within 10 min of L-NMMA administration. Acute hypoxia alone decreased systemic vascular resistance from 1,209 +/- 78 to 992 +/- 58 dynes-s-cm-5 (p < or = 0.05) and increased pulmonary vascular resistance from 92 +/- 11 to 136 +/- 4 dynes-s-cm-5 (p < or = 0.01). While hypoxic conditions were maintained, infusion of L-NMMA increased systemic vascular resistance (to 1,496 +/- 97 dynes-s-cm-5, p < or = 0.01) and increased pulmonary vascular resistance further (to 217 +/- 25 dynes-s-cm-5, p < or = 0.01). CONCLUSIONS: Endothelium-derived nitric oxide contributes to systemic vasodilation and serves as a counterregulatory mechanism to attenuate pulmonary vasoconstriction during acute hypoxia in healthy human subjects.
Assuntos
Hipóxia/fisiopatologia , Óxido Nítrico/fisiologia , Resistência Vascular/fisiologia , Doença Aguda , Adulto , Arginina/análogos & derivados , Arginina/farmacocinética , Arginina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , ômega-N-MetilargininaRESUMO
The reactivity of selected RS-NOs has led to the misconception that these compounds are uniformly unstable under physiological conditions. Moreover, current evidence supports the notion that biological responses elicited by RS-NOs may result from either liberation of nitric oxide or from NO group transfer chemistry involving either NO+ or NO-. Some evidence suggests that such reactions may be enzymatically controlled. The data supporting the potential biological relevance of RS-NOs include: (1) evidence that these compounds form under physiological conditions; (2) their identification in insects, lower mammals, and several human biological systems; and (3) findings that RS-NOs possess a wide range of biological activities, including antimicrobial effects, vasodilation, platelet inhibition, bronchodilation and inhibition of intestinal motility, while being relatively resistant to reactions with O2 and O2- associated with NO. toxicity. It is further noteworthy that biological activity of RS-NO is often not related to the propensity to liberate NO., and these adducts are generally more potent and selective in their action than NO. itself (Stamler et al. 1989; Cooke et al. 1990; Rockett et al. 1991; Jansen et al. 1991; Lipton et al. 1993). The data presented here support the idea that RS-NO may be involved in stabilizing nitric oxide-like bioactivity, in transporting and targeting the NO group to specific (thioregulatory) effector sites, in mitigating the cytotoxic effects of nitric oxide that result from reaction with oxygen species, and may serve to regulate protein function in a posttranslational modification akin, perhaps, to phosphorylation. The recently demonstrated NO group transfer reactions to plasma membrane proteins containing reactive sulfhydryls (Lipton et al. 1993; Stamler 1994) also raises the possibility of signal transduction initiated through more traditional "agonist-receptor" mediated pathways.
Assuntos
Mercaptoetanol , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacologia , Compostos Nitrosos/metabolismo , S-Nitrosotióis , Animais , Fenômenos Químicos , Físico-Química , Humanos , Estrutura Molecular , Óxido Nítrico/toxicidade , Compostos Nitrosos/química , Proteínas/metabolismoRESUMO
The antianginal mechanism of organic nitrates is attributed to their vasodilatory action(s). In this article, the authors review the in vitro and in vivo data implicating an antiplatelet mechanism of action for organic nitrates that may contribute to their antiischemic properties.
RESUMO
Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol contributes to endothelium-derived relaxing factor bioactivity in plasma and vascular smooth muscle. Potentiation of the effects of nitroglycerin by N-acetylcysteine can be attributed to its enhanced biotransformation to an endothelium-derived relaxing factor equivalent, such as nitrosothiol. These observations support the notion of an equilibrium between nitric oxide and nitrosothiol in biological systems that may be influenced by redox state.