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OBJECTIVE: Joint injury involving destabilisation of the joint and damage to the articular cartilage (e.g., sports-related injury) can result in accelerated post-traumatic osteoarthritis (PTOA). Destabilised medial meniscotibial ligament (DMM) surgery is one of the most commonly used murine models and whilst it recapitulates Osteoarthritis (OA) pathology, it does not necessarily result in multi-tissue injury, as occurs in PTOA. We hypothesised that simultaneous cartilage damage and joint destabilisation would accelerate the onset of OA pathology. METHODS: OA was induced in C57BL/6 mice via (a) DMM, (b) microblade scratches of articular cartilage (CS) or (c) combined DMM and cartilage scratch (DCS). Mice were culled 7, 14 and 28 days post-surgery. Microcomputed tomography (µCT) and histology were used to monitor bone changes and inflammation. Dynamic weight bearing, an indirect measure of pain, was assessed on day 14. RESULTS: Osteophytogenesis analysis via µCT revealed that osteophytes were present in all groups at days 7 and 14 post-surgery. However, in DCS, osteophytes were visually larger and more numerous when compared with DMM and cartilage scratch (CS). Histological assessment of cartilage at day 14 and 28, revealed significantly greater damage in DCS compared with DMM and CS. Furthermore, a significant increase in synovitis was observed in DCS. Finally, at day 14 osteophyte numbers correlated with changes in dynamic weight bearing. CONCLUSION: Joint destabilisation when combined with simultaneous cartilage injury accelerates joint deterioration, as seen in PTOA. Thus, DCS provides a novel and robust model for investigating multiple pathological hallmarks, including osteophytogenesis, cartilage damage, synovitis and OA-related pain.
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Cartílago Articular/lesiones , Traumatismos de la Rodilla/complicaciones , Meniscos Tibiales/cirugía , Osteoartritis de la Rodilla/etiología , Animales , Artralgia/etiología , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ratones , Ratones Endogámicos C57BL , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Osteofito/diagnóstico por imagen , Osteofito/etiología , Osteofito/patología , Sinovitis/diagnóstico por imagen , Sinovitis/etiología , Sinovitis/patología , Lesiones de Menisco Tibial , Factores de Tiempo , Soporte de Peso , Microtomografía por Rayos XRESUMEN
BACKGROUND: The characteristics of mature contemporary rapid response systems are unclear. AIM: To determine the patient characteristics, processes and outcomes, both in-hospital and post-discharge, of a well-established rapid response system in a tertiary adult hospital. METHODS: This is a prospective study of consecutive rapid response team (RRT) activations between 1 July and 25 November 2015. Variables included patient characteristics, timing, location and triggers of RRT activations, interventions undertaken, mortality and readmission status at 28 days post-discharge. RESULTS: A total of 1151 RRT activations was analysed (69.1 per 1000 admissions), involving 800 patients, of whom 81.5% were emergency admissions. A total of 351 (30.5%) activations comprised repeat activations for the same patient. Most activations (723; 62.8%) occurred out of hours, and 495 (43%) occurred within 48 h of admission. Hypotension, decreased level of consciousness and oxygen desaturation were the most common triggers. Advanced life support was undertaken in less than 7%; 198 (17.2%) responses led to transfer to higher-level care units. Acute resuscitation plans were noted for only 29.1% of RRT activations, with 80.3% stipulating supportive care only. A total of 103 (12.6%) patients died in hospital, equalling 14 deaths per 100 RRT activations. At 28 days, 150 (18.8%) patients had died, significantly more among those with multiple versus single RRT activations (24.9 vs 16.6%; odds ratio 1.66, 95% confidence interval 1.31-2.44; P = 0.013). CONCLUSION: Relatively few RRT activations are associated with acute resuscitation plans, and most interventions during RRT responses are low level. The high rate of post-RRT deaths and transfers to higher-level care units calls for the prospective identification of such patients in targeting appropriate care.
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Enfermedad Crítica/terapia , Equipo Hospitalario de Respuesta Rápida , Centros de Atención Terciaria , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Benchmarking , Enfermedad Crítica/mortalidad , Femenino , Mortalidad Hospitalaria , Equipo Hospitalario de Respuesta Rápida/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Evaluación de Procesos y Resultados en Atención de Salud , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA.
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Intracellular calcium regulates a number of membrane functions in the erythrocyte, including control of shape, membrane lipid composition and cation permeability. Measurement of total red cell calcium has yielded values between 5 and 15 nmol/ml cells, and these low values in part reflect the absence of Ca2+ -containing organelles. Most intracellular Ca2+ is bound and the low cell ionized Ca2+ concentration (approximately 0.2 microM) is maintained by a combination of low membrane permeability and a powerful Ca2+ -pump. This pump has been identified with a (Ca2+ + Mg2+)-stimulated ATPase, and both Ca2+ transport and ATP splitting are stimulated by calmodulin, a low molecular weight protein which binds Ca2+ avidly and activates many Ca2+ -dependent enzymes. Both high and low affinity kinetics for Ca2+ pumping have been demonstrated, depending on the extent of binding of calmodulin to the pump. A stoichiometry of either 1 or 2 Ca2+ ions pumped per ATP molecule split has been shown, and the value may vary with the level of intracellular Ca2+. Phenothiazines, such as chlorpromazine inhibit the Ca2+ -pump by antagonizing the increment in activity produced by calmodulin. The passive inward leak of Ca2+ into erythrocytes can be quantitated by 45Ca2+ uptake into red cells whose Ca2+ -pump has been inhibited. Estimates of the Ca2+ permeability, based on unidirectional influx, yield values many orders of magnitude lower than for nucleated cells. Influx of Ca2+ into human erythrocytes occurs by a facilitated diffusion process, which can be inhibited by phenothiazines and the cinchona alkaloids. Calcium affects many membrane functions including cation permeability, lipid composition and some cytoskeletal interactions which may determine cell shape. Any rise in intracellular Ca2+ activates a specific K+ channel which normally makes little contribution to K+ fluxes. Kinetic studies of this process demonstrate either high or low affinity Ca2+ -activation of K+ efflux, with low affinity of the channel to Ca2+ being the probable state in vivo. Propranolol is the best known activator of Ca2+ -stimulated K+ efflux, although the mechanism of stimulation is unclear. Like other tissues, red cells possess a Ca2+ -activated phosphoinositol phosphodiesterase. Although it has been suggested that the echinocytic shape change induced by Ca2+ is due to the hydrolysis of polyphosphoinositides, it seems more likely that this shape change results from an effect of Ca2+ on the macromolecular interactions of the cytoskeleton. Abnormal Ca2+ permeability may contribute to red cell destruction in a variety of diseases. For example, in sickle cell anemia a large Ca2+ influx occurs when cells are sickled under deoxy conditions, and moreover, the ability of the Ca2+ -pump to extrude the increment of cell Ca2+ is impaired. Thus, red cell Ca2+ is increased 3-7-fold above normal and this may contribute to the short survival of sickle red cells...
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Calcio/fisiología , Membrana Eritrocítica/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Anemia Hemolítica/metabolismo , Anemia de Células Falciformes/metabolismo , Animales , Calcio/metabolismo , Calmodulina/farmacología , Cationes Bivalentes , Metabolismo Energético/efectos de los fármacos , Humanos , Canales Iónicos/metabolismo , Cinética , Lípidos de la Membrana/metabolismo , Potasio/metabolismo , Talasemia/metabolismoRESUMEN
OBJECTIVE: Driver fatigue accounts for 10-40% of road crashes and is a critical area for public health. As other major road safety issues are more successfully managed, driver fatigue becomes proportionately more important. Both public awareness and legal developments have been slow to reach the same levels as for other road safety risks. The aim of this article is to review countermeasures for non-commercial drivers that are designed to reduce the likelihood of fatigue-related crashes through education and legislation. METHODS: This review outlines information from a wide variety of sources including governments, road safety groups and the scientific literature. Educational and legislative approaches are discussed in terms of both their effectiveness and the associated implications for public health. CONCLUSIONS: Areas for improvement in education include personalising the risk to drivers and developing simple metrics for the self-assessment of fatigue. Legal implications should be more clearly defined and specific laws are needed to more effectively prosecute fatigued drivers who cause crashes. Additional research is needed to further investigate the efficacy of available countermeasures. IMPLICATIONS: Increasingly, road traffic injury is being discussed more broadly as a public health issue. However, the specific issue of driver fatigue still receives less attention than other main causes of road crashes, despite making a significant and comparable contribution to crash rates. Countries such as Australia and New Zealand have a responsibility to counter driver fatigue, as well as other causes of road crashes, and to further pursue improvements for the benefit of public health.
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Accidentes de Tránsito/prevención & control , Conducción de Automóvil/legislación & jurisprudencia , Fatiga , Adolescente , Adulto , Humanos , Australia del SurRESUMEN
OBJECTIVE: The in vitro interaction between sympathetic nerves and basal nitric oxide release was studied in a resistance artery, since these interact powerfully in large vessels. METHODS: The pharmacological interaction between L-NAME and vasoconstriction to field stimulation of sympathetic nerves or exogenous norepinephrine was studied in rabbit cutaneous resistance arteries in wire myographs. RESULTS: Relaxation of norepinephrine-induced tone by acetylcholine, but not sodium nitroprusside, was blocked by N omega-nitro-L-arginine methyl ester (L-NAME: 100 microM), indicating that the agonist-induced release of nitric oxide could oppose the vasoconstrictor effect of norepinephrine and confirming that L-NAME had no effect on endothelium-independent vasodilatation. L-NAME increased norepinephrine potency indicating basal NO release. With short bursts of electrical field stimulation purinergic transmission was dominant at low frequencies and adrenergic at high frequencies. L-NAME had no effect on nerve-mediated responses, even after blocking the purinergic component with alpha,beta-methylene ATP (3 microM), suggesting that the influence of spontaneously released nitric oxide does not extend to the vascular smooth muscle cells under adrenergic nervous control. CONCLUSION(S): This resistance artery exhibits a highly effective nitric oxide-mediated vasodilatation to acetylcholine. It has basal release of nitric oxide which antagonises exogenous norepinephrine. However, basal nitric oxide did not influence adrenergic nerve transmission, which contrasts with previous studies of larger arteries and veins. We speculate that in small resistance arteries there may be a spatial limitation to the zones of vascular smooth muscle influenced by the adrenergic nerves and by basal nitric oxide from the endothelium, respectively. The role of endogenous nitric oxide in modulating vascular tone may thus be less in resistance arteries than in conducting arteries or capacitance vessels and purinergic transmission appears to be particularly resistant.
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Estimulación Eléctrica , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Norepinefrina/farmacología , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Técnicas In Vitro , Masculino , Microscopía Confocal , Nitroprusiato/farmacología , Prazosina/farmacología , Conejos , Piel/irrigación sanguínea , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
Maturational changes in theophylline disposition were evaluated in 52 infants (gestational age, 24 to 40 weeks; postnatal age, 2 to 69 weeks) receiving maintenance theophylline therapy. Theophylline and metabolites were measured in serum and urine at steady state, and the influence of clinical parameters on the maturational changes was analyzed by multiple stepwise linear regression. Theophylline clearance and urine metabolite pattern reached adult values at 55 weeks' postconceptional age. Serum caffeine concentrations greater than 1 microgram/ml occurred in infants up to 50 weeks' postconceptional age. Disappearance of serum caffeine concentrations and maturation of theophylline clearance were primarily related (p < 0.001) to development of the demethylation pathway to 3-methylxanthine. Postconceptional age was the major factor (p < 0.001) explaining the interpatient variability in theophylline clearance (r2 = 0.57), serum caffeine to theophylline ratio (r2 = 0.46), and urinary excretion of theophylline (r2 = 0.51), caffeine (r2 = 0.49), 1,3-methyluric acid (r2 = 0.32), 1-methyluric acid (r2 = 0.53), and 3-methylxanthine (r2 = 0.58). Our findings indicate that postconceptional age rather than postnatal age should be used as a maturational marker during theophylline therapy in infancy.
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Envejecimiento/metabolismo , Teofilina/farmacocinética , Envejecimiento/sangre , Envejecimiento/orina , Análisis de Varianza , Cafeína/sangre , Humanos , Lactante , Recién Nacido , Modelos Lineales , Tasa de Depuración MetabólicaRESUMEN
1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC50: 7.12 +/- 0.19, maximum: 72.1 +/- 0.2.0%) compared to their age-matched controls (pIC50: 5.77 +/- 0.15, maximum: 28.2 +/- 2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7. These results demonstrate that control rat preparations showed greatest sensitivity for ET-1 when set at the lower tension, equivalent to the pressure expected in vivo (approximately 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET(B2) receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.
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Endotelina-1/farmacología , Hipoxia/fisiopatología , Óxido Nítrico/farmacología , Arteria Pulmonar/efectos de los fármacos , Animales , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Hipertensión Pulmonar/fisiopatología , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Wistar , Vasodilatadores/farmacología , Venenos de Víboras/farmacologíaRESUMEN
1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of some antagonists suggests the presence of an inhibitory ET(A)-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activation of ET(A) receptors. SB 209670 is unique in its potency against responses to ET-1 in both control and chronically hypoxic rats, as well as human, isolated pulmonary resistance arteries.
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Hipoxia/fisiopatología , Arteria Pulmonar/fisiología , Receptores de Endotelina/fisiología , Resistencia Vascular/fisiología , Animales , Enfermedad Crónica , Antagonistas de los Receptores de Endotelina , Endotelina-1/antagonistas & inhibidores , Endotelina-1/farmacología , Endotelina-3/antagonistas & inhibidores , Endotelina-3/farmacología , Humanos , Técnicas In Vitro , Indanos/farmacología , Masculino , Contracción Muscular/fisiología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Ratas , Ratas Wistar , Receptores de Endotelina/agonistas , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide. Experimental hypoxia had differential effects on all three agonists and did not mimic the effect of nitric oxide synthase inhibition.
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Agonistas alfa-Adrenérgicos/farmacología , Endotelio Vascular/fisiología , Oxígeno/fisiología , Arteria Pulmonar/fisiología , Receptores Adrenérgicos alfa/fisiología , Vasoconstricción , Animales , Arginina/análogos & derivados , Arginina/farmacología , Tartrato de Brimonidina , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , NG-Nitroarginina Metil Éster , Norepinefrina/farmacología , Fenilefrina/farmacología , Arteria Pulmonar/efectos de los fármacos , Quinoxalinas/farmacología , Conejos , Vasoconstricción/efectos de los fármacosRESUMEN
1. Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150-200 microns, i.d.). 2. Cumulative concentration-response curves to ET-1, sarafotoxin 6c (SX6c) and ET-3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA-selective), BMS 182874 (ETA-selective) and BQ-788 (ETB-selective). 3. All agonists induced concentration-dependent contractions. However, the response curves to ET-1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET-1. Above 1 nM ET-1 the response curve was markedly steeper. Maximum responses to ET-3 and SX6c were the same as those to 1 nM ET-1 and 30% of those to 0.1 microM ET-1. The order of potency, taking 0.3 microM as a maximum concentration was SX6c >> ET-3 > ET-1 (pEC50 values of: 10.75 +/- 0.27, 9.05 +/- 0.19, 8.32 +/- 0.08 respectively). Taking 1 nM ET-1 as a maximum, the EC50 for ET-1 was 10.08 +/- 0.13 and therefore ET-1 was equipotent to ET-3 and SX6c over the first component of the response curve. 4. Responses to ET-1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ-788. Conversely, responses to ET-1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ-788. 5. The results suggest that at concentrations up to 1 nM, responses to ET-1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.
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Arteria Pulmonar/efectos de los fármacos , Receptores de Endotelina/fisiología , Vasoconstricción/efectos de los fármacos , Endotelinas/farmacología , Humanos , Técnicas In Vitro , Oligopéptidos/farmacología , Piperidinas/farmacología , Arteria Pulmonar/fisiología , Receptor de Endotelina A , Receptor de Endotelina B , Venenos de Víboras/farmacologíaRESUMEN
1. The effects of nitric oxide (10(-6) M), N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M, an inhibitor of nitric oxide synthase), endothelium removal, hypoxia and selective alpha-adrenoceptor antagonists on responses to nerve electrical field-stimulation (EFS) were studied in the rabbit isolated pulmonary artery. 2. EFS induced frequency-dependent contractions which were abolished by prazosin (alpha 1-adrenoceptor antagonist) and unaffected by rauwolscine (alpha 2-adrenoceptor antagonist). EFS-induced responses were potentiated by L-NAME and inhibited by nitric oxide. The effect of L-NAME was reversed by the presence of L-arginine (2 x 10(-4) M), which had no effect on its own. In the presence of L-NAME, the EFS-induced responses were reduced by rauwolscine and the residual responses were abolished by prazosin. 3. Removal of the vascular endothelium increased the maximum contractile response to EFS but did not inhibit the ability of L-NAME to potentiate contractile responses to EFS. 4. Hypoxia inhibited the contractile response to EFS. This effect of hypoxia was also seen in the presence of L-NAME and in endothelium rubbed preparations. 5. In conclusion, the endothelium modulates EFS-induced contractions in the rabbit pulmonary artery. The contraction induced by EFS was inhibited by nitric oxide, but potentiated by the nitric oxide-synthase inhibitor, L-NAME. The effect of L-NAME was not mediated solely through the endothelium and revealed involvement of alpha 2-adrenoceptors in EFS-induced contraction. Hypoxia inhibited neurogenic responses in rabbit isolated pulmonary arteries.
Asunto(s)
Endotelio Vascular/fisiología , Oxígeno/fisiología , Arteria Pulmonar/inervación , Transmisión Sináptica , Vasoconstricción , Antagonistas Adrenérgicos alfa/farmacología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Estimulación Eléctrica , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , NG-Nitroarginina Metil Éster , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiología , Conejos , Transmisión Sináptica/efectos de los fármacos , Vasoconstricción/efectos de los fármacosRESUMEN
1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor
Asunto(s)
Hipertensión Pulmonar/metabolismo , Arteria Pulmonar/fisiología , Agonistas de Receptores de Serotonina/farmacología , Vasoconstricción/fisiología , Animales , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Hipertensión Pulmonar/fisiopatología , Técnicas In Vitro , Ketanserina/farmacología , Masculino , Cloruro de Potasio/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Ratas , Ratas Wistar , Serotonina/farmacología , Antagonistas de la Serotonina/farmacologíaRESUMEN
To determine whether lung injury causes increased plasma prostaglandin (PG) levels, 35 rabbits received oleic acid and 35 served as controls. Half of each group also received 4 ml/kg of Intralipid over one hour and at least five in each subgroup received indomethacin 7.5 mg/kg. Arterial and venous plasma concentrations of PGE2, 6-keto-PGF1 alpha, and PGF2 alpha-M were measured. Venous PGE2 was significantly higher in the oleic acid-injured than in the normal lung group, 1560 +/- 270 (Mean +/- SEM) versus 880 +/- 140 pg/ml (p less than .05). Plasma levels were reduced by 50% with indomethacin, but PGE2 levels remained significantly higher than in the normal lung group, 850 +/- 180 versus 480 +/- 60 for arterial (p less than .05) and 820 +/- 140 versus 480 +/- 80 for venous (p less than .05), respectively. PGF2 alpha-M levels were significantly higher in the lung injury group, 240 +/- 50 versus 50 +/- 40 pg/ml for arterial (p less than .05) and 220 +/- 50 versus 95 +/- 40 for venous (p less than .05), respectively. These lung injury-related increases in PGE2 and PGF2 alpha-M appear related both to increased pulmonary production and to decreased pulmonary clearance. With Intralipid infusion, however, arterial PGE2 increased by 500 +/- 260 pg/ml compared to baseline (p less than .05) with no change in venous PGE2, indicating in this instance that the increase in arterial PGE2 levels is related to increased pulmonary production.
Asunto(s)
Enfermedades Pulmonares/inducido químicamente , Ácidos Oléicos/toxicidad , Prostaglandinas/sangre , Animales , Indometacina/farmacología , Enfermedades Pulmonares/sangre , ConejosRESUMEN
Recordings of breathing movements and heart rate (pneumograms) were obtained prospectively in 89 preterm infants at 0-28 days of age to determine if those who develop apnea and/or bradycardia with cyanosis (Group 1) differ from those who do not (Group 2). The 148 pneumograms were blindly analyzed for periodic breathing, bradycardia, longest apnea, and quiet time. Pneumograms were compared between groups at weekly intervals during the first 4 weeks. Significant differences were found among infants who had pneumograms recorded during the 1st week of life. Although mean gestational age and mean postconceptional age at recording were similar, birthweight and weight at recording were significantly lower in Group 1 infants. Total time spent in periodic breathing and the longest episode of periodic breathing were significantly greater in Group 1 infants. Logistic regression analysis revealed significant independent relationships between birthweight and periodic breathing at less than or equal to 7 days of age and the occurrence of symptomatic apnea and/or bradycardia. It is concluded that preterm infants who develop apnea and/or bradycardia with cyanosis have a lower mean birthweight and mean weight at recording at less than or equal to 7 days of age than similar asymptomatic preterm infants. Periodic breathing at less than or equal to 7 days of age is associated with the occurrence of clinical symptoms of apnea and/or bradycardia. Normal pneumogram values for groups of 6-21 asymptomatic preterm infants are provided for the first 4 weeks of life.
Asunto(s)
Apnea/diagnóstico , Bradicardia/diagnóstico , Recién Nacido de Bajo Peso/fisiología , Enfermedades del Prematuro/diagnóstico , Recien Nacido Prematuro/fisiología , Monitoreo Fisiológico/métodos , Apnea/fisiopatología , Peso al Nacer , Bradicardia/fisiopatología , Edad Gestacional , Humanos , Recién Nacido , Enfermedades del Prematuro/fisiopatología , Monitoreo Fisiológico/instrumentación , Estudios ProspectivosRESUMEN
Collagen is an essential component of connective tissue and is present in the pulmonary interstitium. Collagen deposition is known to increase in many acquired chronic diseases, including bronchopulmonary dysplasia (BPD). Urinary excretion of hydroxyproline has been used as a specific index of collagen synthesis. Many studies have demonstrated that dexamethasone therapy is associated with respiratory improvement in infants with BDP but the mechanism of this effect is not well understood. We postulated that in infants with BDP who receive dexamethasone, suppression of collagen synthesis may cause respiratory improvement. Therefore, we studied the effect of dexamethasone on respiratory status and urinary excretion of hydroxyproline in 14 ventilator-dependent infants with BDP. Infants received 0.5 mg/kg/day dexamethasone, tapered by half every 3 days to complete a 12 day course. Eleven of the 14 infants were extubated at a mean +/- SD of 8.7 +/- 4.9 days after starting dexamethasone. Mean urinary hydroxyproline/creatinine ratios at 3, 6, 9, and 12 days of dexamethasone therapy were significantly lower than the mean pretreatment value, but after discontinuation rapidly rose toward baseline values. Decreased urinary excretion of hydroxyproline indicates that dexamethasone suppressed collagen synthesis in these infants. We speculate that suppression of collagen synthesis reduced pulmonary inflammation and fibrosis, resulting in respiratory improvement.
Asunto(s)
Displasia Broncopulmonar/terapia , Dexametasona/uso terapéutico , Respiración Artificial , Displasia Broncopulmonar/orina , Colágeno/biosíntesis , Colágeno/efectos de los fármacos , Terapia Combinada , Creatinina/orina , Dexametasona/farmacología , Femenino , Humanos , Hidroxiprolina/efectos de los fármacos , Hidroxiprolina/orina , Lactante , Recién Nacido , MasculinoRESUMEN
Cord blood caffeine concentrations were measured by high-pressure liquid chromatography in 79 preterm infants. Eleven infants (14%) had detectable caffeine concentrations ranging from 1.1 to 3.7 micrograms/mL (means +/- SD = 2.5 +/- 0.8), and 68 infants had no measurable caffeine. Seven infants with detectable caffeine (group 1) had impedance pneumograms recorded before 2 weeks of age. Each infant in group 1 was matched with two infants without detectable caffeine by birthweight, gestational age, and chronologic age at pneumogram recording to yield a control group (group 2) of 14 infants. Comparison of the groups using quantitative measures of apnea, bradycardia, and periodic breathing obtained from pneumogram analysis and the incidence of monitor alarms on bedside nursing records showed no significant differences. Thus, caffeine was present infrequently and at low concentrations at birth in 79 preterm infants. The amount of apnea, bradycardia, and periodic breathing experienced before 2 weeks of age in 7 preterm infants with detectable cord blood caffeine was not different from that in 14 similar infants without caffeine. Future studies are planned to examine the relationship between postnatal changes in transplacentally acquired methylxanthine concentrations and quantitative measures of apnea, bradycardia, and periodic breathing in a larger number of preterm infants without cardiorespiratory disease.
Asunto(s)
Apnea/inducido químicamente , Bradicardia/inducido químicamente , Cafeína/sangre , Respiración de Cheyne-Stokes/inducido químicamente , Sangre Fetal/análisis , Recien Nacido Prematuro/fisiología , Intercambio Materno-Fetal , Trastornos Respiratorios/inducido químicamente , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Recién Nacido , Embarazo , Respiración/efectos de los fármacos , Pruebas de Función RespiratoriaRESUMEN
In a previous study we found that pain and discomfort caused a marked increase in skin blood flow in newborn infants, and that skin blood flow decreased after morphine. In this study we tested morphine effect on the skin blood flow response to pain more systematically. Skin blood flow was measured using a laser Doppler technique during 19 percutaneous central venous catheter placements in 18 infants, 10 of whom received intravenous morphine premedication. The mean +/- SD baseline skin blood flow was similar between the two groups: 22.5 +/- 9.5 ml 100 g-1 min-1 in the morphine group, and 23.7 +/- 8.0 ml 100 g-1 min-1 in the no-morphine group, respectively (p = n.s.). During PCVC placement in the morphine treated group, skin blood flow remained low with minimal variability. The mean value was 22.6 +/- 7.7 ml 100 g-1 min-1 (p = n.s. compared to baseline). In 7/9 infants not treated with morphine skin blood flow increased dramatically during PCVC placement, while in two it did not. But the mean skin blood flow in this group of 9 infants during PCVC placement was 45.3 +/- 34 ml 100 g-1 min-1, an overall change of 97% increase from the baseline. This was statistically significant compared with the baseline and the morphine group value during PCVC insertion (p < 0.04). During the 45 min time period after PCVC placement, skin blood flow values between groups again were similar. We conclude that morphine pretreatment for PCVC placement minimizes pain-associated increases in skin blood flow. The issue of whether skin blood flow changes could serve as measures of adequate analgesia needs to be evaluated with further studies.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Morfina/uso terapéutico , Dolor/tratamiento farmacológico , Piel/irrigación sanguínea , Análisis de Varianza , Cateterismo Periférico , Estudios de Evaluación como Asunto , Humanos , Recién Nacido , Variaciones Dependientes del Observador , Dolor/fisiopatología , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
Recalling a past experience often requires the suppression of related memories that compete with the retrieval target, causing memory impairment known as retrieval-induced forgetting. Two experiments examined how retrieval-induced forgetting varies with the similarity of the competitor and the target item (target-competitor similarity) and with the similarity between the competitors themselves (competitor-competitor similarity). According to the pattern-suppression model (M. C. Anderson & B. A. Spellman, 1995), high target-competitor similarity should reduce impairment, whereas high competitor-competitor similarity should increase it. Both predictions were supported: Encoding target-competitor similarities not only eliminated retrieval-induced forgetting but also reversed it, whereas encoding competitor-competitor similarities increased impairment. The differing effects of target-competitor and competitor-competitor similarity may resolve conflicting results concerning the effects of similarity on inhibition.
Asunto(s)
Inhibición Psicológica , Memoria , Práctica Psicológica , Adulto , Femenino , Generalización Psicológica , Humanos , Masculino , Recuerdo Mental , Modelos PsicológicosRESUMEN
AIMS: To investigate factors that may contribute to performance adaptation during permanent night work. METHODS: Fifteen healthy subjects participated in an adaptation and baseline night sleep, directly followed by seven simulated eight-hour night shifts (2300 to 0700 hours). At the end of each shift they were taken outside and exposed to natural light for 20 minutes. They then slept from approximately 0800 hours until they naturally awoke. RESULTS: There was a significant increase in mean performance on a visual psychomotor vigilance task across the week. Daytime sleep quality and quantity were not negatively affected. Total sleep time (TST) for each of the daytime sleeps was reduced, resulting in an average cumulative sleep debt of 3.53 hours prior to the final night shift. TST for each of the daytime sleep periods did not significantly differ from the baseline night, nor did TST significantly vary across the week. There was a significant decrease in wake time after sleep onset and sleep onset latency across the week; sleep efficiency showed a trend towards greater efficiency across the consecutive daytime sleeps. Hours of wakefulness prior to each simulated night shift significantly varied across the week. The melatonin profile significantly shifted across the week. CONCLUSIONS: Results suggest that under optimal conditions, the sleep debt that accumulates during consecutive night shifts is relatively small and does not exacerbate decrements in night-time performance resulting from other factors. When sleep loss is minimised, adaptation of performance during consecutive night shifts can occur in conjunction with circadian adaptation.