Asunto(s)
Centros Médicos Académicos/tendencias , Conducta Cooperativa , Descubrimiento de Drogas/tendencias , Industria Farmacéutica/tendencias , Centros Médicos Académicos/métodos , Animales , Descubrimiento de Drogas/métodos , Industria Farmacéutica/métodos , Predicción , Humanos , Terapias en Investigación/métodos , Terapias en Investigación/tendenciasRESUMEN
Drug discovery might be better termed drug invention. Discoveries take place globally, and many arise from academia and research institutes. The job of the biotechnology and pharmaceutical industry is to identify those that stand the greatest chance of being turned into medicines to improve health-in other words, to invent a practical outcome on the basis of discovery. In this commentary we identify some of the areas in which molecular medicine has had the greatest impact and continues to change the invention of medicines.
Asunto(s)
Medicina Clínica/tendencias , Diseño de Fármacos , Industria Farmacéutica/tendencias , Biología Molecular/tendencias , Farmacogenética/tendencias , Farmacología Clínica/tendencias , Animales , Predicción , Genómica/tendencias , Genotipo , Humanos , Selección de Paciente , Farmacocinética , Fenotipo , Reproducibilidad de los ResultadosRESUMEN
Prediction of cardiovascular (CV) complications represents the Achilles' heel of end-stage renal disease. Surrogate markers of endothelial dysfunction have been advocated as predictors of CV risk in this cohort of patients. We have recently adapted a noninvasive laser Doppler flowmetry (LDF) functional testing of endothelium-dependent microvascular reactivity and demonstrated that end-stage renal disease patients are characterized by profound alterations in thermal hyperemic responsiveness. We hypothesized that such functional assessment of the cutaneous microcirculation may offer a valid, noninvasive test of the severity of endothelial dysfunction and CV risk. To test this hypothesis, we performed a cross-sectional study, in which we compared LDF measurements to conventional risk factors, and performed a pilot longitudinal study. LDF studies were performed in 70 patients and 33 controls. Framingham and Cardiorisk scores were near equivalent for low-risk patients, but more divergent as risk increased. C reactive protein (CRP) levels and LDF parameters (amplitude of thermal hyperemia (TH), area under the curve of TH) showed significant abnormality in high-risk vs low-risk patients calculated using either Framingham or Cardiorisk scores. Patients who had abnormal LDF parameters showed increased CV mortality, however, had similar risk assessments (Framingham, Cardiorisk, CRP, and homocysteine) to those with unimpaired LDF tracings. In conclusion, LDF parameters of microvascular reactivity offer a sensitive characterization of endothelial dysfunction, which may improve CV risk assessment through incorporation into the Framingham or Cardiorisk algorithm.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Endotelio Vascular/fisiopatología , Fallo Renal Crónico/complicaciones , Flujometría por Láser-Doppler , Termogénesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Proteína C-Reactiva/análisis , Capilares/citología , Capilares/fisiopatología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Medición de RiesgoRESUMEN
Endothelium-derived nitric oxide (NO) plays an important role in transducing the effects of angiogenic factors. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase (NOS). We used a murine model of hindlimb ischemia to investigate whether genetic or metabolic changes in ADMA levels could impair angiogenic response in vivo. Hindlimb ischemia was surgically induced in C57BL/6J mice, apo E-deficient mice, or transgenic mice overexpressing dimethylarginine dimethylaminohydrolase (DDAH). Some animals were also treated with the NOS antagonist L-nitro-arginine, or the NO precursor L-arginine. Angiogenesis was quantified in the hindlimb skeletal muscle by capillary/myocyte ratio. Plasma or tissue ADMA levels were measured by HPLC. In normal mice, hindlimb ischemia increased tissue ADMA twofold, and reduced DDAH and NOS expression. This was associated with a reduced NOS activity (by over 80%) three days following surgery. On day seven, a threefold increase in DDAH expression and a fall in tissue ADMA levels were associated with a sevenfold increase in NOS activity, whereas NOS expression did not increase above baseline. In DDAH transgenic mice, the elevation of ADMA and decrement in NOS activity was blunted during hindlimb ischemia. Plasma ADMA levels were increased in apo E-mice (1.79 +/- 0.45 versus 1.07 +/- 0.08 pmol/l; p = 0.008). Capillary index was significantly reduced in apo E-mice up to seven weeks after surgery (0.25 +/- 0.05 versus 0.62 +/- 0.08; p < 0.001). The effect of hypercholesterolemia on capillary index was reversed by L-arginine, and (in wild-type mice) mimicked by administration of the NOS antagonist L-nitro-arginine. In conclusion, metabolic or genetic changes in plasma and tissue ADMA levels affect tissue NO production and angiogenic response to ischemia.
Asunto(s)
Arginina/análogos & derivados , Arginina/fisiología , Neovascularización Fisiológica/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Arginina/análisis , Western Blotting , Modelos Animales de Enfermedad , Femenino , Hipercolesterolemia/fisiopatología , Isquemia/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Although deep venous thrombosis (DVT) is now widely managed on an outpatient basis, at a practical level there remains a potential for uncertainty as to which patient might prove suitable and in particular in regard to the lines of responsibility of each department involved in the delivery of clinical care. This guideline sets out recommendations for the standardization of the outpatient management of patients with DVT.
Asunto(s)
Atención Ambulatoria/normas , Manejo de Atención al Paciente/normas , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/terapia , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Estudios de Seguimiento , Hemostasis/efectos de los fármacos , Humanos , Rol de la Enfermera , Reino Unido , Trombosis de la Vena/sangreRESUMEN
BACKGROUND: Chronic periodontitis causes a low-grade systemic inflammatory response; its standard treatment, however, induces an acute inflammatory response. The aim of this study was to describe the systemic inflammatory reactions to an intensive periodontal treatment regimen. METHODS: Fourteen otherwise healthy subjects suffering from severe chronic periodontitis were enrolled in a 1 month pilot single-blind trial. Intensive periodontal treatment, consisting of full-mouth subgingival root debridement delivered within a 6-h period, was performed. Periodontal parameters were recorded before and 1 month after completion of treatment. Blood samples were taken at baseline and 1, 3, 5, 7 and 30 days after treatment. Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6) and C-reactive protein (CRP) serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Complete blood counts were also performed. RESULTS: One day after treatment, mild neutrophilia and monocytosis (p < 0.05) and lymphopenia (p < 0.01) were accompanied by a sharp increase in inflammatory markers (IL-1Ra, IL-6, p < 0.01). A 10-fold increase in CRP (p < 0.001) was detected on day 1 and its kinetics followed a pattern of a classical acute phase response (significantly raised concentrations up to 1 week, p < 0.01). At 3-7 days after treatment, subjects presented also with a mild tendency towards a normocytic anaemic state (p < 0.01) and a degree of lympho-thrombocytosis (p < 0.05). The observed changes were similar to those expected following the well-characterized endotoxin-challenge model of inflammation. CONCLUSIONS: Intensive periodontal treatment produced an acute systemic inflammatory response of 1 week duration and might represent an alternative to classic endotoxin-challenge or drug-induced models to study acute inflammation in humans.
Asunto(s)
Reacción de Fase Aguda/etiología , Raspado Dental/efectos adversos , Modelos Biológicos , Periodontitis/terapia , Reacción de Fase Aguda/sangre , Análisis de Varianza , Recuento de Células Sanguíneas , Proteína C-Reactiva/análisis , Enfermedad Crónica , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Periodontitis/sangre , Proyectos Piloto , Estudios Prospectivos , Sialoglicoproteínas/sangre , Método Simple Ciego , Estadísticas no ParamétricasRESUMEN
BACKGROUND AND PURPOSE: Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5' flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160). METHODS: Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO(x)) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis. RESULTS: The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86; P=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (P=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO(x) levels were associated with the T-786C locus (P=0.03) but only in the presence of the intron 4a allele (P=0.07 for interaction). CONCLUSIONS: The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.
Asunto(s)
Infarto Encefálico/genética , Isquemia Encefálica/genética , Haplotipos/genética , Óxido Nítrico Sintasa/genética , Polimorfismo Genético/genética , Anciano , Alelos , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Infarto Encefálico/fisiopatología , Isquemia Encefálica/fisiopatología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Intrones/genética , Masculino , Microcirculación/fisiopatología , Persona de Mediana Edad , Nitratos/sangre , Óxido Nítrico Sintasa de Tipo III , Nitritos/sangre , Oportunidad Relativa , Valor Predictivo de las Pruebas , Radiografía , Medición de Riesgo , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.
Asunto(s)
Amidohidrolasas/biosíntesis , Amidohidrolasas/genética , Endotelio/metabolismo , Variación Genética , Regiones Promotoras Genéticas , Secuencia de Bases , Enfermedades Cardiovasculares/genética , Clonación Molecular , Islas de CpG , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Óxido Nítrico/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Isoformas de Proteínas , Factores de Tiempo , Transcripción Genética , TransfecciónRESUMEN
A common polymorphism of the endothelial NO synthase gene that predicts a Glu298Asp amino acid substitution in the mature protein has been associated with cardiovascular disorders in which NO bioactivity is impaired. However, the influence of this polymorphism on endothelial function is unknown. Healthy pregnancy is associated with enhanced endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery, a response mediated by NO. In this study, we investigated the effect of the endothelial NO synthase Glu298Asp polymorphism on endothelium-dependent vasodilation in early pregnancy, making the hypothesis that any genotype-dependent differences in NO generation would be more marked during pregnancy, when the production of NO is upregulated. FMD of the brachial artery was recorded during the first trimester in 139 healthy women with normal singleton pregnancies genotyped for the Glu298Asp variant of endothelial NO synthase. Maternal FMD exhibited a codominant inverse relation with the number of Asp298 alleles (r=-0.21, P=0.01). Among homozygotes for endothelial NO synthase Asp298, FMD (7.99+/-1.46%) was significantly lower than that observed among individuals homozygous for endothelial NO synthase Glu298 (10.12+/-3.44) (P=0.002). In a backward stepwise multiple regression analysis, vessel size (P<0.0001) and Glu298Asp polymorphism (P=0.01) were significantly and independently correlated with FMD. Our findings indicate that the endothelial NO synthase Glu298Asp polymorphism is associated with differences in endothelium-dependent dilation at 12-week gestation and are the first to implicate genetic factors in the normal vascular adaptation to pregnancy. They also provide a potential mechanism linking the endothelial NO synthase polymorphism with the development of cardiovascular disorders and have implications for understanding the genetic basis of preeclampsia.
Asunto(s)
Endotelio Vascular/enzimología , Óxido Nítrico Sintasa/genética , Embarazo/fisiología , Vasodilatación/fisiología , Adaptación Fisiológica , Adulto , Arteria Braquial/diagnóstico por imagen , Femenino , Genotipo , Humanos , Polimorfismo Genético/fisiología , Primer Trimestre del Embarazo , UltrasonografíaRESUMEN
20 years ago, an academic biomedical scientist or clinician who set up a company would probably have been perceived by colleagues as "on the make" and rather unacademic-"not one of us", in other words. Nowadays, academics who have started companies are commonplace, and in some universities the businessman-academic is becoming the norm, although still far more common in the USA than in Europe. At best, the opportunity to capitalise on a discovery has the potential to motivate research workers, provide greater funding for research, and ultimately create wealth. At worst, the spawning of a company from within academia has the potential to use public employees, space, and equipment for personal gain, and divert academics from the pursuit of profound scientific questions into more immediate product-driven research or even marketing dressed up as research. Here, I discuss some of the issues surrounding biotechnology and spin-off companies originating in academia.
Asunto(s)
Academias e Institutos/tendencias , Biotecnología/tendencias , Industrias/tendencias , Propiedad Intelectual , Investigación/economía , Biotecnología/economía , Ética , HumanosRESUMEN
OBJECTIVE: To investigate the concentration of markers of inflammation in non-pregnant women, women with normal pregnancy and women with pre-eclampsia. METHODS: Pregnant women (n=26), women with pre-eclampsia (n=25) and non-pregnant normotensive women (n=21) were included in the study. C-reactive protein was measured by latex-enhanced immunoturbidimetric assay, serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by high sensitivity ELISA. Kruskal-Wallis non-parametric analysis of variance followed by the Mann-Whitney U-test were used for statistical analyses. RESULTS: Higher values (mean+/-S.E.M.) of C-reactive protein were found in pre-eclampsia (4.11+/-0.37 mg/dl) compared with normal pregnant women (2.49+/-0.26 mg/dl) and non-pregnant controls (1.33+/-0.15 mg/dl). TNF-alpha was significantly higher in women with pre-eclampsia (15.74+/-5.09 pg/ml), in relation to the control group (2.76+/-0.41 pg/ml) and women with normal pregnancy (8.31+/-1.55 pg/ml). IL-6 levels were significantly higher in pre-eclamptic women (12.91+/-1.29 pg/ml) compared with normal pregnant (5.07+/-0.423 pg/ml) and control women (1.25+/-0.13 pg/ml). CONCLUSIONS: The results of this cross-sectional study in a high-risk Andean population show that both C-reactive protein and pro-inflammatory cytokines are present in higher concentrations in women with pre-eclampsia. The study was undertaken in women with established pre-eclampsia and it is not possible to determine whether the increased concentrations of C-reactive protein and pro-inflammatory cytokines were a cause or consequence of the disease.
Asunto(s)
Proteína C-Reactiva/análisis , Interleucina-6/sangre , Preeclampsia/sangre , Factor de Necrosis Tumoral alfa/análisis , Adulto , Análisis de Varianza , Presión Sanguínea , Estudios Transversales , Ecuador , Ensayo de Inmunoadsorción Enzimática , Femenino , Edad Gestacional , Humanos , Recuento de Leucocitos , Paridad , EmbarazoRESUMEN
OBJECTIVES: We examined to what extent the variation in risk factors for coronary heart disease (CHD) and the Framingham risk score (FRS) explain the variation in vascular reactivity in adults aged 30 to 53 years. BACKGROUND: The role of risk factors in determining vascular reactivity in the general population has not been quantified. METHODS: Risk factors for CHD were measured, and the FRS was calculated in 69 healthy volunteers. Lipoprotein particle size was measured using proton-nuclear magnetic resonance spectroscopy. Forearm plethysmography was used to assess blood flow responses to acetylcholine (ACh), bradykinin (BK), glyceryl trinitrate (GTN), noradrenaline and N(G)-monomethyl-L-arginine (L-NMMA). RESULTS: Lower ACh and BK responses were associated with a higher body mass index (BMI), a higher total cholesterol to high-density lipoprotein (HDL) cholesterol ratio, lower HDL cholesterol and a cigarette smoking habit (all p < 0.05). Higher low-density lipoprotein (LDL) cholesterol was also associated with a lower BK response (p = 0.001). A decreased GTN response was associated with a higher BMI and total cholesterol to HDL cholesterol ratio (both p < 0.05). A decreased L-NMMA response was associated with a smoking habit (p < 0.001). Lipoprotein particle sizes did not independently predict any vascular response. A high FRS was associated with a reduced response to ACh (p = 0.07), BK (p = 0.003) and L-NMMA (p = 0.003), and the relationship was stronger in women than in men. Altogether, risk factors explained 13%, 9%, 8% and 15% of the response to ACh, BK, GTN and L-NMMA, respectively. CONCLUSIONS: Lipids, BMI and smoking are important determinants of vascular reactivity. The FRS is predictive of agonist-stimulated, endothelium-dependent vasodilation and basal NO release. However, much of the variation in the vascular responses to these drugs, at this age, remains unexplained.
Asunto(s)
Circulación Coronaria/fisiología , Enfermedad Coronaria/fisiopatología , Endotelio Vascular/fisiopatología , Resistencia Vascular/fisiología , Adulto , Índice de Masa Corporal , Colesterol/sangre , Estudios de Cohortes , Enfermedad Coronaria/etiología , Femenino , Humanos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/efectos adversosRESUMEN
Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO(x)) in middle-aged men. We also determined whether plasma NO(x) or NOS 3 genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4 NOS 3 gene polymorphisms: -786 T/C, -922 A/G, 894 G/T (which predicts a Glu(298)-->Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NO(x) was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the NOS 3 polymorphismsstudied, with the strongest allelic association being detected between -922 A/G and -786 T/C polymorphisms in the gene promoter (Delta=0.90, P<0.001). Plasma NO(x) was lower in smokers than in nonsmokers in the North Mymms (10.8+/-4.5 versus 11.8+/-4.6 micromol/L, P=0.13), Chesterfield (8.4+/-3.6 versus 9.9+/-4.0 micromol/L, P=0.01), and random samples (10.7+/-5.1 versus 11.7+/-4.7 micromol/L, P=0.03). A weak but significant inverse relationship was detected between plasma NO(x) and serum cholesterol only in the North Mymms data set (r=-0.14, P=0.02). No relationship was detected between plasma NO(x) and any of the NOS 3 polymorphisms, nor was there any association between any NOS 3 polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that NOS 3 genotype does not influence significantly the level of plasma NO(x) or the risk of IHD in this population sample of middle-aged British men.
Asunto(s)
Isquemia Miocárdica/etiología , Óxido Nítrico Sintasa/genética , Óxidos de Nitrógeno/sangre , Presión Sanguínea , Estudios de Casos y Controles , Colesterol/sangre , Estudios de Cohortes , Frecuencia de los Genes , Genotipo , Humanos , Desequilibrio de Ligamiento , Persona de Mediana Edad , Isquemia Miocárdica/sangre , Isquemia Miocárdica/genética , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III , Polimorfismo Genético , Estudios Prospectivos , Factores de Riesgo , Fumar/efectos adversosRESUMEN
The treatment of HIV-positive patients with protease inhibitors has been suggested to increase their risk of atherosclerosis. The cause of this accelerated atherogenesis is unknown, but on the basis of previous studies we postulated that it could be linked to the presence of human herpesvirus-8. A retrospective analysis of post-mortem reports showed a strong correlation between Kaposi's sarcoma and the presence of atheroma. This hypothesis merits further investigation.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Arteriosclerosis/etiología , Autopsia , Herpesvirus Humano 8 , Sarcoma de Kaposi/complicaciones , Adulto , Animales , Enfermedades Cardiovasculares/etiología , Bovinos , Gammaherpesvirinae , Infecciones por Herpesviridae/complicaciones , Humanos , Masculino , Estudios RetrospectivosRESUMEN
Nitric oxide (NO) appears to play a role in modulating cardiac function in both health and disease. Early studies in isolated rodent cardiac myocytes demonstrated a depressant effect of NO supplied by NO donors (exogenous) as well as NO generated within myocytes (endogenous). There is increasing evidence for a functional NO generating system within the human myocardium, which appears upregulated in certain disease states. Induction of the high output nitric oxide synthase isoform (iNOS) has been demonstrated in the failing myocardium, though its functional significance remains unproven. More recently published data have contradicted the notion that NO acts solely as a negative inotrope demonstrating positive inotropy in both isolated rodent and human ventricular myocytes in response to a range of NO donors. Different NO donors have different NO release kinetics and generate a range of NO species (NO., NO+ and NO-) which may interact at a number of subcellular targets. The observed response of any cardiac preparation to an NO donor represents the net effect of activation of different effector targets and may explain the contradictory reported effects of NO. To realise the therapeutic potential of NO will require specific targeting at a subcellular level.
Asunto(s)
Endocardio/efectos de los fármacos , Contracción Miocárdica/fisiología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/fisiología , Depresión Química , Endocardio/metabolismo , Inducción Enzimática , Humanos , Contracción Miocárdica/efectos de los fármacos , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Estimulación QuímicaRESUMEN
Myogenic tone is an important determinant of vascular tone and blood flow in small resistance arteries of certain vascular beds. The role of the endothelium in myogenic responses is unclear. We hypothesized that endothelium-derived NO release modulates myogenic constriction in small resistance arteries and that mesenteric small arteries from mice with targeted disruption of the gene for endothelial NO synthase (eNOS) (knockout mice) demonstrate greater myogenic tone than do wild-type mice. Third-order mesenteric arteries (approximately 200 micrometer) were isolated and mounted in a pressure myograph. Internal diameter was recorded over a pressure range of 10 to 80 mm Hg. Removal of the endothelium significantly (P<0.05) enhanced the magnitude of myogenic constriction in wild-type mice. Similarly, pretreatment of arteries with N(G)-nitro-L-arginine methyl ester (L-NAME; 300 micromol/L) produced a comparable significant (P<0.05) increase in myogenic tone, whereas indomethacin (5 micromol/L) had no effect. eNOS knockout arteries also exhibited myogenic constriction. Neither L-NAME nor indomethacin had any effect on myogenic tone in the arteries of eNOS knockout mice. However, blockade of potential endothelium-derived hyperpolarizing factor-like mechanisms via inhibition of K(+) flux using either apamin (100 nmol/L) with charybdotoxin (100 nmol/L), Ba(2+) (30 micromol/L) with ouabain (1 mmol/L), or 18alpha-glycyrrhetinic acid (100 micromol/L) significantly (P<0.01) enhanced myogenic constriction. This study demonstrates that basal endothelium-derived NO modulates myogenic tone in mesenteric small arteries of wild-type mice. However, eNOS knockout arteries display normal myogenic responsiveness despite the absence of basal NO activity. The data suggest that this compensatory effect is due to the activity of an endothelium-derived hyperpolarizing factor to normalize vascular tone.
Asunto(s)
Factores Biológicos/fisiología , Arterias Mesentéricas/fisiología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/metabolismo , Vasoconstricción/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Apamina/farmacología , Bario/farmacología , Calcio/farmacología , Caribdotoxina/farmacología , Endotelio Vascular/fisiología , Inhibidores Enzimáticos/farmacología , Femenino , Genotipo , Ácido Glicirretínico/análogos & derivados , Técnicas In Vitro , Indometacina/farmacología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Penicilamina/análogos & derivados , Penicilamina/farmacología , Bloqueadores de los Canales de Potasio , Resistencia Vascular , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
Nitric oxide (NO)--a 1:1 combination of the two most abundant gaseous elements--is a biological mediator of complexity, subtlety and protean effects. The history of its discovery as a mediator is fascinating, and its role in mammalian biology and medicine is proving to be of fundamental importance.
Asunto(s)
Óxido Nítrico/fisiología , Vasodilatadores/farmacología , Animales , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Electroquímica , Humanos , Óxido Nítrico/análisis , Óxido Nítrico/biosíntesis , Óxido Nítrico/farmacología , Vasodilatadores/análisisRESUMEN
BACKGROUND: Circulating inhibitors of endothelial function have been implicated in the pathogenesis of vascular disease in chronic renal failure. The aim of this study was to determine if lowering the plasma concentration of these and other dialysable toxins improves endothelial function. To do this we compared the acute effects on endothelial function of single episodes of haemodialysis with automated peritoneal dialysis. We hypothesized that endothelial function would improve after dialysis, with a greater effect seen after haemodialysis due to more substantial clearance of endothelial toxins per-treatment. METHODS: Subjects with end-stage renal failure undergoing haemodialysis (n=16) or automated peritoneal dialysis (n=14) were investigated. Endothelial function was determined using vascular ultrasound to measure flow-mediated dilatation of the brachial artery and was compared with the dilatation caused by sublingual glyceryl trinitrate. Endothelial function was assessed before and after a single dialysis treatment. Plasma concentrations of the inhibitors of endothelial function, asymmetric dimethyl-l-arginine and homocysteine were measured. Flow-mediated dilatation was expressed as percentage change from basal diameter and analysed using Student's t test. RESULTS: The plasma concentration of circulating inhibitors of endothelial function was reduced after haemodialysis but not peritoneal dialysis. Haemodialysis increased flow-mediated dilatation from 4.0+/-1.0% to 5.8+/-1.2% (P<0.002). These changes persisted for 5 h but returned to baseline by 24 h. Automated peritoneal dialysis had no acute effect on flow-mediated dilatation (5.9+/-1.1% vs 5.4+/-0.8% after, P>0.5). There were no effects of either dialysis modality on dilatation to glyceryl trinitrate. CONCLUSIONS: Short-term reduction of circulating inhibitors of endothelial function by haemodialysis is associated with increased flow-mediated dilatation. These data suggest that dialysable endothelial toxins have deleterious effects on endothelial function that are rapidly reversible.