RESUMEN
The crystal structure of a dimeric 2:2:2 FGF:FGFR:heparin ternary complex at 3 A resolution has been determined. Within each 1:1 FGF:FGFR complex, heparin makes numerous contacts with both FGF and FGFR, thereby augmenting FGF-FGFR binding. Heparin also interacts with FGFR in the adjoining 1:1 FGF:FGFR complex to promote FGFR dimerization. The 6-O-sulfate group of heparin plays a pivotal role in mediating both interactions. The unexpected stoichiometry of heparin binding in the structure led us to propose a revised model for FGFR dimerization. Biochemical data in support of this model are also presented. This model provides a structural basis for FGFR activation by small molecule heparin analogs and may facilitate the design of heparin mimetics capable of modulating FGF signaling.
Asunto(s)
Factores de Crecimiento de Fibroblastos/química , Heparina/química , Receptores de Factores de Crecimiento de Fibroblastos/química , Sitios de Unión , Cristalografía , Dimerización , Factores de Crecimiento de Fibroblastos/metabolismo , Heparina/metabolismo , Enlace de Hidrógeno , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Sulfatos/química , Sulfatos/metabolismoRESUMEN
A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth factor receptor 1 (FGFR1) and showed differential specificity toward other receptor tyrosine kinases. Crystal structures of the tyrosine kinase domain of FGFR1 in complex with the two compounds were determined. The oxindole occupies the site in which the adenine of adenosine triphosphate binds, whereas the moieties that extend from the oxindole contact residues in the hinge region between the two kinase lobes. The more specific inhibitor of FGFR1 induces a conformational change in the nucleotide-binding loop. This structural information will facilitate the design of new inhibitors for use in the treatment of cancer and other diseases in which cell signaling by tyrosine kinases plays a crucial role in disease pathogenesis.
Asunto(s)
Inhibidores Enzimáticos/metabolismo , Piperazinas/metabolismo , Proteínas Tirosina Quinasas/química , Pirroles/metabolismo , Proteínas Tirosina Quinasas Receptoras , Receptores de Factores de Crecimiento de Fibroblastos/química , Células 3T3 , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Fosforilación , Fosfotirosina/metabolismo , Piperazinas/química , Piperazinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Pirroles/química , Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Receptor de Insulina/antagonistas & inhibidores , Receptor de Insulina/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
A reliable high-performance liquid chromatography (HPLC) method is described for the separation of dimethylamino-azobenzenesulfonyl-amino acid (DABS-AA). The separation is accomplished by reversed-phase chromatography on a Hypersil ODS column (4.6 x 150 mm) with a Hewlett-Packard liquid chromatography system. In addition to the developed sample and solvent preparation procedure, this precolumn modification method using dimethylaminoazobenzene sulfonyl chloride (DABS-CL) for amino acid analysis is proved reliable and sensitive. Five apolipoprotein B-100 tryptic peptides, two of them containing cysteine, were demonstrated as examples for the general application of this method in amino acid analysis. It is a useful method for analysis of cysteine- and cystine-containing peptide and, furthermore, for determination of sulfhydryl and disulfide linkages of proteins.
Asunto(s)
Aminoácidos/análisis , Apolipoproteínas B/química , Cromatografía Líquida de Alta Presión/métodos , p-Dimetilaminoazobenceno/análogos & derivados , Secuencia de Aminoácidos , Apolipoproteína B-100 , Cromatografía Líquida de Alta Presión/instrumentación , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Tripsina , p-Dimetilaminoazobenceno/químicaRESUMEN
The effect of the intra-arterial injection of 5 to 10 microng of sodium nitroprusside on the caliber of normal and diseased coronary arteries was evaluated in 21 patients during diagnostic cardiac catheterization. In addition, the effect of intra-graft injection of 5 microng of the same agent on the blood flow in aorta-right coronary artery saphenous vein bypass grafts was also evaluated intra-operatively in two patients. The compound induced an increase in the caliber of both normal and stenosed coronary arteries as well as an increase of flow in the grafts. Consistent with measurements of coronary flow response to sodium nitroprusside, angina pectoris which developed in four patients during cardiac catheterization was immediately relieved and the ischemic ST-segment depression significantly reversed after injection of 5 to 10 microng of the drug into the left main coronary artery. Within the dose range used, the drug caused no significant effect on systemic blood pressure or apparently deleterious electrophysiologic changes. No side effects were observed. We conclude that the primary direct action of sodium nitroprusside in the human coronary artery is vasodilatory.
Asunto(s)
Angina de Pecho/fisiopatología , Vasos Coronarios/efectos de los fármacos , Ferricianuros/farmacología , Nitroprusiato/farmacología , Sistema Vasomotor/efectos de los fármacos , Adulto , Anciano , Angina de Pecho/tratamiento farmacológico , Arteriopatías Oclusivas/fisiopatología , Cateterismo Cardíaco , Angiografía Coronaria , Puente de Arteria Coronaria , Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/fisiopatología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitroprusiato/uso terapéutico , Vena Safena/trasplante , Trasplante AutólogoRESUMEN
The efficacy of potassium canrenoate in suppressing frequent ventricular premature depolarizations and ventricular bigeminal and trigeminal rhythms thought to be due to digitalis overdose was studied in seven men and five women (average age, 54.5 years). A mean dose of 525 mg. (1.31 mEq.) of potassium canrenoate administered intravenously effectively suppressed the ventricular rhythm disturbances in eight of the 12 patients for from several minutes to 4 hours. The mean serum digoxin level determined in seven patients was greater than 2.3 ng. per milliliter. The ability of potassium canrenoate to counteract digitalis intoxication suggests that the molecule of canrenoate is unique in the clinical setting since it shows both diuretic and antiarrhythmic properties.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/inducido químicamente , Ácido Canrenoico/uso terapéutico , Glicósidos Digitálicos/envenenamiento , Pregnadienos/uso terapéutico , Adulto , Anciano , Antiarrítmicos/administración & dosificación , Ácido Canrenoico/administración & dosificación , Digoxina/sangre , Diuréticos/administración & dosificación , Humanos , Persona de Mediana Edad , Fibrilación Ventricular/inducido químicamente , Fibrilación Ventricular/tratamiento farmacológicoRESUMEN
Effects of hemodynamic parameters of heart rate were studied in 19 patients with low cardiac output syndrome following open heart surgery for mitral and/or aortic valve replacement in the first five postoperative days. The central venous pressure (CVP), left atrial mean pressure (LAMP), and arterial blood pressures were determined at spontaneous heart rate (SHR), and during graded atrial (12 pts.) or ventricular (7 pts.) pacing each day. An "optimal pacing rate" (OPR), characterized by the most advantageous arterial pressures at the possible lowest levels of CVP and LAMP, and by the suppression of preexisting arrhythmias, if any, was established daily for maintaining each patient on that rate. The SHR was 69 +/- 9 and the OPR was 102 +/- 9 on the first postoperative day. For the fifth postoperative day the SHR was 68 +/- 10 and the OPR decreased to 90 +/- 9. Pacing with the OPR significantly increased cardiac performance. E.g. the hemodynamic improvement on the first postoperative day induced by pacing was comparable to the spontaneous improvement seen during the first five postoperative days. The hemodynamic effect of atrial pacing on circulation was more definitive than that of ventricular pacing. Since OPR may be significantly higher than SHR and varies from day to day, we suggest that, in cases where pacing is applied to improve cardiac performance, it be determined for each patient individually each postoperative day.
Asunto(s)
Frecuencia Cardíaca , Enfermedades de las Válvulas Cardíacas/cirugía , Prótesis Valvulares Cardíacas , Hemodinámica , Marcapaso Artificial , Adolescente , Adulto , Presión Sanguínea , Presión Venosa Central , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Cuidados Posoperatorios , Pulso Arterial , Factores de TiempoRESUMEN
Blood flow in aortocoronary saphenous vein grafts was studied in response to intragraft injection of sodium nitroprusside and papaverine hydrochloride. Following injection of 50 mug of sodium nitroprusside, mean graft flow increased from 40.1 +/- 4.5 to 81.3 +/- 8.5 ml per minute. Administration of 30 mg of papaverine hydrochloride caused mean graft flow to rise from 35.4 +/- 3.9 to 70 +/- 7.9 ml per minute. Sodium nitroprusside increases aortocoronary graft flow, the doubling effect of 50 mug of the drug being of the same order of magnitude as that induced by 30 mg of papaverine hydrochloride.
Asunto(s)
Puente de Arteria Coronaria , Circulación Coronaria/efectos de los fármacos , Ferricianuros/farmacología , Nitroprusiato/farmacología , Vena Safena , Vasodilatadores/farmacología , Venas/trasplante , Adulto , Anciano , Velocidad del Flujo Sanguíneo , Evaluación de Medicamentos , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Nitroprusiato/administración & dosificación , Papaverina/farmacologíaRESUMEN
Bipolar electrode catheter recordings of His bundle electrograms with three simultaneously recorded surface electrocardiographic leads were obtained from 30 pediatric and adolescent patients (aged 3 to 18 years). In 14 patients, cardiac murmurs were proved to be innocent by cardiac catheterization. The control conduction intervals were compared to those of 13 patients with congenital heart disease, and three with acquired heart disease (myocardiopathy, rheumatic valvular disease, and Friedreich's ataxia). P-R, intra-atrial (P-A), A-V nodal (A-H), and intraventricular (H-V) conduction intervals were measured to the nearest 5 msec. Conduction delays were analyzed in each of the three components of the P-R interval. These delays occurred both in single components of the system as well as in combined conduction delays and were not always demonstrable by surface electrocardiograms. The Wenckebach phenomenon induced by atrial pacing was localized to the A-V node as well as the His-Purkinje system. This technique of intracardiac electrogram recordings is safe, does not significantly prolong cardiac atheterization time, and often yields unique and useful data concerning A-V conduction.
Asunto(s)
Nodo Atrioventricular/fisiopatología , Fascículo Atrioventricular/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Adolescente , Cateterismo Cardíaco , Niño , Preescolar , Electrocardiografía , Femenino , Auscultación Cardíaca , Cardiopatías Congénitas/fisiopatología , Cardiopatías/fisiopatología , Frecuencia Cardíaca , Humanos , MasculinoRESUMEN
The effects of potassium canrenoate on arrhythmias induced by long-term progressive digoxin toxicity were studied in eight conscious beagle dogs. Sinus bradycardia and sinoatrial block, as well as atrioventricular (A-V) conduction disturbances, were consistently alleviated by administration of potassium canrenoate. Premature supraventricular (including junctional) and ventricular depolarizations as well as ventricular tachycardias were also suppressed. Although potassium canrenoate always terminated the digitalis-induced arrhythmias, it usually converted the rhythm to sinus arrhythmia rather than to normal sinus rhythm. Equimolar sodium canrenoate, but not potassium chloride, had similar reversal effects on arrhythmias induced by long-term digoxin intoxication. These data indicate that canrenoate, a diuretic agent with reported positive inotropic effects, may be useful in the treatment of digitalis-induced arrhythmias in man.
Asunto(s)
Digoxina , Diuréticos/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides , Pregnadienos/uso terapéutico , Animales , Arritmia Sinusal/tratamiento farmacológico , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/tratamiento farmacológico , Nodo Atrioventricular/fisiopatología , Bradicardia/tratamiento farmacológico , Fascículo Atrioventricular/fisiopatología , Diuréticos/farmacología , Perros , Electrocardiografía , Femenino , Bloqueo Cardíaco/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Cetosteroides/uso terapéutico , Masculino , Potasio/uso terapéutico , Cloruro de Potasio/uso terapéutico , Sodio/uso terapéutico , Taquicardia/tratamiento farmacológicoRESUMEN
The antiarrhythmic effects of 4 pteridine analogues, 2 of which are potassium-sparing diuretics, triamterene (2, 4, 7-triamino-6-phenylpteridine) and [2-phenyl-4, 7 diaminopteridine-6-(N-diethylaminoethyl) carboxamide] and 2 of which have no diuretic effects [2-phenyl-4, 7-diaminopteridine-6-(N-2-hydroxyethyl) carboxamide], on ouabain-induced ventricular tachycardia in intact pentobarbital-anesthetized dogs were investigated. Ouabain was given as a continuous infusion 2 mug/kg/min intravenously until 5 min after the onset of a sustained ventricular tachycardia. It was found that both 6-(N-dimethylaminopropyl) and 6-(N-diethylaminoethyl) carboxamide derivates of the pteridine had a significant protective effect against ouabain-induced ventricular tachycardia in dogs that had been pretreated with a dose of 5 mg/kg intravenously. At this dose the 2 pteridine compounds with diuretic activity exhibited a transient antiarrhythmic effect in abolishing the ouabain-induced ventricular tachycardia while those without diuretic properties failed to suppress the ventricular tachycardia.
Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Ouabaína/envenenamiento , Pteridinas/uso terapéutico , Animales , Arritmias Cardíacas/inducido químicamente , Nodo Atrioventricular/efectos de los fármacos , Depresión Química , Perros , Electrocardiografía , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Concentración de Iones de Hidrógeno , Taquicardia/inducido químicamente , Triantereno/uso terapéuticoRESUMEN
The electrophysiologic effects of the antiarrhythmic agent disopyramide phosphate given intravenously were studied in 10 patients with cardiac disease. Studies included determinations of sinus recovery time and refractoriness of the atria, the atrioventricular (A-V) node and the His-Purkinje system. Measurements were performed at rest and 15 and 30 minutes after administration of disopyramide. Serum drug levels were measured at these times. Sinus recovery time was shortened at both 15 and 30 minutes, with an average decrease of 39.5 and 146.2 msec, respectively (P less than 0.01). Atrial refractoriness was not altered significantly, but tended to be reduced; the mean effective refractory period was 289.5 msec before administration of disopyramide and 259 and 270 msec 15 and 30 minutes, respectively, after administration. The functional refractory period of the atrioventricular (A-V) node was definitely prolonged in seven patients 15 minutes after administration of disopyramide. The relative refractory period of the His-Purkinje System was not altered. Although this study does not elucidate the mechanism by which disopyramide acheives its antiarrhythmic effects, animal work has shown that it is similar to that of quinidine. In the doses used the drug does not seem to cause first, second or third degree A-V block or fascicular or bundle branch block; it did not increase the severity of first degree A-V block in the three patients with this disturbance. The drug may be particularly useful when arrhythmias are associated with slow sinus rates.
Asunto(s)
Disopiramida/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Piridinas/farmacología , Adulto , Factores de Edad , Anciano , Arritmias Cardíacas/tratamiento farmacológico , Fibrilación Atrial/tratamiento farmacológico , Bloqueo de Rama/tratamiento farmacológico , Enfermedad Coronaria/tratamiento farmacológico , Disopiramida/administración & dosificación , Disopiramida/sangre , Electrofisiología , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Periodo Refractario ElectrofisiológicoRESUMEN
The inotropic action of tolbutamide previously demonstrated in vitro was evaluated in 15 nondiabetic subjects during diagnostic cardiac catheterization. Following bolus injection of 250 mg of tolbutamide intravenously, a rise of serum insulin and a slight fall of serum potassium were observed. Inotropic response was determined from significant fall in PEP/LVET ratio, significant fall of left ventricular end-diastolic pressure, shift to an augmented function curve in work-pressure relationships, and prominent rise of dP/dt values at comparable heart rates. The inotropic effect was greatest at 5-15 min with return to near control values at 30 min. An unusually marked inotropic response was observed in one subject. While the measurable net hemodynamic effect of tolbutamide in the human heart is small, its effect on ischemic and normal areas within the heart of a diabetic patient with atherosclerosis may be different. Thus, its ultimate effect on the diseased heart may be significant.