RESUMEN
OBJECTIVE: Plasma concentrations of B-type natriuretic peptide (BNP) and troponin are often measured for diagnostic purposes when patients are admitted with heart failure, but their prognostic value when measured soon after admission is uncertain. We aimed to investigate the added prognostic value of admission measurements of BNP and troponins in patients with acute heart failure. METHODS AND RESULTS: Multivariable prognostic models for death or any worsening heart failure (WHF) or rehospitalization for WHF by 30 days, 30-day death or rehospitalization for WHF, and 90-day mortality were constructed using baseline data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS) including BNP and troponin I. Of 1347 patients, the median (interquartile range) value of BNP was 422 (156-945) pg/mL and 855 (63%) had measurable troponin I. By 30 days, 432 patients had died or experienced WHF. Clinical variables had only moderate predictive performance that was not substantially improved by BNP or troponin I (c-indices 0.6528 and 0.6595, respectively). By 30 days, 150 patients died or were rehospitalized for WHF. The c-index using clinical variables (0.6855) was not improved by adding biomarkers. By 90 days, 135 patients had died. The c-index for mortality was somewhat better than for composite outcomes (0.7394) but improved little with biomarkers (0.7461). CONCLUSION: Routine clinical data recorded at the time of admission in patients with acute heart failure are poor at predicting recurrent admissions but somewhat better at predicting mortality. Neither BNP nor troponin measured at admission improved predictions; measurement closer to discharge, or of other novel biomarkers, might perform differently.
Asunto(s)
Insuficiencia Cardíaca/sangre , Péptido Natriurético Encefálico/sangre , Admisión del Paciente , Piridinas/administración & dosificación , Receptores de Endotelina/efectos de los fármacos , Tetrazoles/administración & dosificación , Troponina I/sangre , Enfermedad Aguda , Anciano , Biomarcadores/sangre , Relación Dosis-Respuesta a Droga , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Mortalidad Hospitalaria/tendencias , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Alta del Paciente/tendencias , Pronóstico , Receptores de Endotelina/sangre , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Factores de Tiempo , Estados Unidos/epidemiología , Vasodilatadores/administración & dosificaciónRESUMEN
XK is a putative transporter of unknown function that is ubiquitously expressed and linked through disulfide bonds to Kell protein, an endothelin-3 (ET-3)-converting enzyme. We generated three knockout (KO) mice that lacked either Xk, Kell or both proteins and characterized erythrocyte cation levels, transport and hematological parameters. Absence of Xk or Kell was accompanied by changes in erythrocyte K(+), Mg(2+), Na(+) and Ca(2+) transport that were associated with changes in mean cellular volume and corpuscular hemoglobin concentration mean. Baseline Ca(2+)-ATPase activity was undetected in erythrocytes from all three mouse types but was restored upon pre-incubation with ET-3. Consistent with these alterations in Ca(2+) handling, we observed increased Gardos channel activity in Kel and Xk KO mice. In addition Kel deletion was associated with increased Mg(2+) permeability while Xk deletion blocked Na/Mg exchanger activity. Our results provide evidence that cellular divalent cation regulation is functionally coupled to the Kell/XK system in erythrocytes and loss of this complex may contribute to acanthocytosis formation in McLeod syndrome.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/fisiología , Cationes Bivalentes/sangre , Eritrocitos/metabolismo , Sistema del Grupo Sanguíneo de Kell/fisiología , Abetalipoproteinemia/sangre , Abetalipoproteinemia/genética , Acantocitos , Sistemas de Transporte de Aminoácidos Neutros/sangre , Sistemas de Transporte de Aminoácidos Neutros/deficiencia , Sistemas de Transporte de Aminoácidos Neutros/genética , Animales , Antiportadores/sangre , Calcio/sangre , ATPasas Transportadoras de Calcio/sangre , Endotelina-3/farmacología , Volumen de Eritrocitos , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hemólisis/genética , Homeostasis , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/sangre , Transporte Iónico , Sistema del Grupo Sanguíneo de Kell/genética , Magnesio/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Complejos Multiproteicos , Neuroacantocitosis , Potasio/sangre , Receptores de Endotelina/sangre , Sodio/sangreRESUMEN
Pulmonary arterial hypertension [PAH] is a rare but well-known cardiovascular condition potentially associated with human immunodeficiency virus [HIV] infection and is currently recognized to be one of the most ominous noninfectious HIV complications. Although there is no clear evidence supporting the use of any medication for the treatment of HIV-related PAH, many of the currently available agents have been shown to exert some clinical benefits HIV-PAH patients. To date, no data are available regarding the potential effects of sitaxsentan, a selective endothelin type-A receptor antagonist, in this peculiar patient population. We report the case of a successful switch to sitaxsentan in a HIV-infected patient with PAH initially receiving bosentan who developed a late treatment-related side-effect.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Infecciones por VIH/complicaciones , VIH , Hipertensión Pulmonar/tratamiento farmacológico , Isoxazoles/uso terapéutico , Tiofenos/uso terapéutico , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/etiología , Masculino , Persona de Mediana Edad , Presión Esfenoidal Pulmonar/efectos de los fármacos , Receptores de Endotelina/sangreRESUMEN
Pulmonary arterial hypertension (PAH) is a rare fatal disease. Current disease-specific therapeutic interventions in PAH target 1 of 3 established pathways in disease pathobiology: prostacyclin, nitric oxide, and endothelin-1. Endothelin receptor antagonists (ERAs) act on the endothelin pathway by blocking binding of endothelin-1 to its receptors (endothelin type-A [ET(A)] and/or type-B [ET(B)]) on the surface of endothelial and smooth muscle cells. Ambrisentan is an oral, once-daily, ET(A)-selective ERA in development for the treatment of PAH. In Phase 3 clinical trials in patients with PAH, ambrisentan (2.5-10 mg orally once-daily) improved exercise capacity, Borg dyspnea index, time to clinical worsening, WHO functional class, and quality of life compared with placebo. Ambrisentan provided durable (at least 2 years) improvement in exercise capacity in a Phase 2 long-term extension study. Ambrisentan was well tolerated with a lower incidence and severity of liver function test abnormalities compared with the ET(A)/ET(B) ERA, bosentan, and the ET(A)-selective ERA, sitaxsentan. Ambrisentan does not induce or inhibit P450 enzymes; therefore, ambrisentan is unlikely to affect the pharmacokinetics of P450-metabolized drugs. The demonstration of clinical efficacy, low incidence of acute hepatic toxicity, and low risk of drug-drug interactions support the role of ambrisentan for the treatment of PAH.
Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Fenilpropionatos/uso terapéutico , Piridazinas/uso terapéutico , Antagonistas de los Receptores de Endotelina , Endotelina-1/sangre , Endotelina-1/efectos de los fármacos , Ejercicio Físico/fisiología , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/fisiopatología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Fenilpropionatos/farmacocinética , Presión Esfenoidal Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/fisiología , Piridazinas/farmacocinética , Receptores de Endotelina/sangre , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacosRESUMEN
We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET(A) and ET(B) receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h(-1)), in the absence and presence of the ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade decreased PVR but only during exercise (at 4 km h(-1), from 3.0 +/- 0.1 to 2.3 +/- 0.1 mmHg min l(-1); P Asunto(s)
Estado de Conciencia/fisiología
, Hipertensión Pulmonar/etiología
, Hipertensión Pulmonar/fisiopatología
, Infarto del Miocardio/complicaciones
, Infarto del Miocardio/fisiopatología
, Receptores de Endotelina/fisiología
, Animales
, Presión Sanguínea/efectos de los fármacos
, Presión Sanguínea/fisiología
, Antagonistas de los Receptores de Endotelina
, Endotelina-1/farmacología
, Femenino
, Hemodinámica/efectos de los fármacos
, Hemodinámica/fisiología
, Hipertensión Pulmonar/sangre
, Masculino
, Infarto del Miocardio/sangre
, Condicionamiento Físico Animal/fisiología
, Circulación Pulmonar/efectos de los fármacos
, Circulación Pulmonar/fisiología
, Piridinas/farmacología
, Receptores de Endotelina/sangre
, Descanso/fisiología
, Porcinos
, Tetrazoles/farmacología
, Vasoconstricción/fisiología
, Vasodilatadores/farmacología
RESUMEN
Secondary pulmonary arterial hypertension (SPAH) is an adverse outcome of a variety of systemic disorders. These include collagen vascular diseases, chronic thromboembolism, human immunodeficiency virus, portopulmonary hypertension, and other diseases. Progression of SPAH may persist despite stabilization of the causative disease, thereby contributing to the poor quality of life and unfavorable survival in these patients. Treatment of the underlying cause and oxygen supplementation may alleviate symptoms, but no specific therapy to treat SPAH currently exists. Endothelin receptor blockade with bosentan has been shown to be beneficial in the treatment of primary pulmonary hypertension, but efficacy of this therapy in SPAH has not been established. We describe a case series of 6 patients with disparate causes of SPAH, who benefited from endothelin receptor blockade therapy. The causes of SPAH included collagen vascular disease (scleroderma) (1); systemic lupus erythematosus (2); chronic thromboembolic disease (2); and granulomatous vasculitis from sarcoidosis (1). Therapy with bosentan led to improvements in symptoms, New York Heart Association functional class, and walking distance in all patients. Distance walked in 6 minutes increased from a mean of 151.67 +/- 69.30 m at baseline to 314.83 +/- 89.09 m after an average of 14 months of bosentan treatment. Pulmonary arterial pressure decreased in most but not all 6 patients on follow-up echocardiography. This case series suggests a role for endothelin receptor blockade therapy in SPAH and should generate further interest in pharmacologic management of SPAH. A prospective controlled clinical trial of bosentan in SPAH is urgently needed.
Asunto(s)
Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina , Hipertensión Pulmonar/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Anciano , Bosentán , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/etiología , Lupus Eritematoso Sistémico/complicaciones , Masculino , Persona de Mediana Edad , Presión Esfenoidal Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/fisiología , Receptores de Endotelina/sangre , Sarcoidosis Pulmonar/complicaciones , Esclerodermia Sistémica/complicaciones , Tromboembolia/complicacionesRESUMEN
The synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<0.10 nM). Further screening of these compounds by assessing the plasma exposures at 1 h, 4 h, and 8 h after oral administration (3 or 10 mg/kg) in rats led to identification of the hydroxymethyl (2i) and 3-methoxy-2-methylpropyl (2u) derivatives exhibiting good oral bioavailability in rats.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Piridinas/química , Piridinas/metabolismo , Receptores de Endotelina/metabolismo , Animales , Humanos , Unión Proteica/fisiología , Piridinas/sangre , Conejos , Ratas , Receptores de Endotelina/sangre , Relación Estructura-ActividadRESUMEN
SUMMARY: Efficacy of a new, potent non-selective endothelin antagonist, l-753037, was examined in a model of canine coronary artery occlusion and reperfusion to assess whether blockade of both ETA and ETB receptors would enhance or reduce myocardial ischemic injury. Instrumented dogs were randomized to receive vehicle (n = 9) or l-753037 (0.1 microg/kg/min, n = 9) by intracoronary infusion 30 minutes before a 90-minute LCx coronary artery occlusion and through 4 hours of reperfusion. After 4 hours of reperfusion, plasma ET-1 levels rose significantly in both groups: 24 +/- 3 fmol/ml in vehicle animals (P < 0.01) versus 42 +/- 5 fmol/ml with l-753037 (P < 0.05). Treatment with l-753037 normalized total LCx flow and regional myocardial flow after 4 hours of reperfusion in all regions. LCx flow was reduced 16% from pre-occlusion baseline (P = 0.45) with treatment compared with 35% with vehicle (P < 0.01). Endocardial flow in the risk region returned to baseline values with l-753037 treatment but was reduced approximately 50% in vehicle animals. l-753037 treatment was associated with a 38% reduction in infarct size (24.1 +/- 3.9% AAR with l-753037 treatment versus 38.7 +/- 3.1% with vehicle, P < 0.01). Thus, a non-selective endothelin antagonist provides significant myocardial protection primarily by improving regional myocardial flow distribution following reperfusion and demonstrated no detrimental effects associated with blockade of the ETB receptor.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Isquemia Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Piridinas/uso terapéutico , Animales , Enfermedad Coronaria/sangre , Enfermedad Coronaria/terapia , Perros , Receptores de Endotelina/sangreAsunto(s)
Cardiomiopatía Dilatada/genética , Receptores de Endotelina/genética , Biomarcadores/sangre , Cardiomiopatía Dilatada/sangre , Cardiomiopatía Dilatada/mortalidad , Humanos , Músculo Liso Vascular/irrigación sanguínea , Músculo Liso Vascular/metabolismo , Polimorfismo Genético/genética , Valor Predictivo de las Pruebas , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/sangre , Análisis de SupervivenciaRESUMEN
Endothelin-1 (ET-1) is a peptide with potent vasopressor and mitogenic actions. Moreover, ET-1 displays modulatory effects on the endocrine system, including stimulation of angiotensin II and aldosterone production, and influences ion and fluid transport in the gut and kidney. A number of groups reported that ET-1 is overexpressed in the vasculature in several salt-sensitive models of experimental hypertension. African Americans present with a salt-sensitive and low-renin model of hypertension, and circulating plasma ET-1 levels are significantly increased in this population. The prevalence of hypertension and its complications is also higher in Blacks than in Whites and, despite extensive research, the reasons for this difference are not well understood. We propose that vasoactive, mitogenic, and renal effects of the ET system might contribute to the development, maintenance and/or complications of hypertension in African Americans.
Asunto(s)
Endotelina-1/fisiología , Hipertensión/etnología , Receptores de Endotelina/fisiología , Negro o Afroamericano , Animales , Endotelina-1/sangre , Hemodinámica , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Riñón/irrigación sanguínea , Riñón/fisiopatología , Prevalencia , Receptor de Endotelina B , Receptores de Endotelina/sangre , Cloruro de Sodio Dietético , Estados Unidos , Sistema Vasomotor/fisiopatologíaRESUMEN
OBJECTIVE: Earlier, we reported that high insulin incubation in vitro leads to increased ETA receptor expression in cultured rat aortic smooth muscle cells (Diabetes 1998, 47: 934-944). Our later observation of enhanced endothelin-1 evoked vasoconstriction in aorta from the hyperinsulinemic obese Zucker rat indicated that this interaction might also be relevant in vivo. To further examine the relationship between insulinemia and endothelin, we characterized endothelin receptor expression and endothelin-1 peptide levels in vascular tissues and plasma from young and old obese Zucker rats. METHODS: 12 and 40-week-old Zucker obese and lean rats were used. Plasma endothelin-1 levels and endothelin-1 peptide content in the mesenteric artery and in the thoracic aorta were examined by radioimmunoassay. Messenger RNA levels of endothelin-1 peptide and ETA and ETB receptors were examined in the aortic and mesenteric vessels using RT-PCR. RESULTS: Obese rats from both age groups had significantly higher plasma levels of insulin (4-10 fold), total cholesterol (2-3 fold), triglycerides (10-fold), and glucose (approximately 1.5 fold) than their lean counterparts. There was a trend toward worsening lipoproteinemia and glycemia, but improved insulinemia with age in the obese rats. In association with these changes, obese rats exhibited attenuated endothelin-1 peptide and preproET-1 mRNA levels, but conversely elevated ETA and ETB receptor mRNA levels in both aortic and mesenteric vessels. CONCLUSION: These data suggest that vascular tissue from the metabolically dysregulated obese Zucker rat exhibits attenuated endothelin-1 peptide production and elevated endothelin receptor levels. Since elevated insulin levels have been linked to increased endothelin receptor expression, it is plausible that hyperinsulinemia upregulates endothelin receptors contributing to elevated vasoconstrictor responses to endothelin-1 in this model of obesity and hypertension.
Asunto(s)
Aorta Torácica/química , Endotelina-1/análisis , Hiperinsulinismo/metabolismo , Resistencia a la Insulina , Arterias Mesentéricas/química , Obesidad/metabolismo , Comunicación Paracrina , Animales , Southern Blotting , Endotelina-1/sangre , Endotelina-1/genética , Masculino , ARN Mensajero/análisis , Ratas , Ratas Zucker , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/análisis , Receptores de Endotelina/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The liver is a major site of synthesis, clearance, and actions of the powerful vasoactive peptide endothelin-1 (ET-1). We investigated the role of the liver in ET-1 homeostasis by comparing circulating and hepatic ET-1 levels and hepatic ET receptors in patients undergoing orthotopic liver transplantation (OLTx) for end-stage liver disease (ESLD) with those in patients undergoing liver resection for focal lesions with otherwise normal hepatic synthetic function. Central venous and radial arterial blood was drawn immediately after induction of anesthesia (point I), 10 minutes before beginning of resection or the anhepatic stage (point II), and 30 minutes after completion of resection or reperfusion of the grafted liver (point III). Portal and hepatic venous blood was drawn at points II and III. Plasma ET-1 levels were higher in ESLD patients than in resection patients. Plasma ET-1 levels rose both during resection and transplantation; the increase in ET-1 was more pronounced during transplantation. In ESLD patients, hepatic venous ET-1 was higher than portal venous ET-1, suggesting reduced clearance and/or enhanced synthesis of the peptide in the cirrhotic liver. Conversely, hepatic venous ET-1 was lower than portal venous ET-1 in resection patients at all time points and at point III in the ESLD patients. Hepatic concentration of ET-1 was greater and the capacity of the liver to catabolize ET-1 was reduced in ESLD patients as compared to the resection patients. Further, hepatic ET receptor density was higher in ESLD than in resection patients. These results suggest that the cirrhotic liver may contribute to elevated plasma ET-1 in ESLD. Considering its potent hemodynamic and metabolic effects in the liver, increased hepatic ET-1 and ET receptors and plasma ET-1 could play a role in the pathophysiology of liver disease and perioperative complications of OLTx.
Asunto(s)
Endotelina-1/sangre , Hepatectomía , Homeostasis/fisiología , Fallo Hepático/cirugía , Trasplante de Hígado/fisiología , Receptores de Endotelina/sangre , Adulto , Anciano , Biopsia con Aguja , Técnicas de Cultivo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Probabilidad , Pronóstico , Sensibilidad y EspecificidadRESUMEN
The blood concentration of three representative endothelin and four neurokinin receptor antagonists were monitored both at the portal and jugular vein of rats 30, 60 and 90 min after oral administration. Peptide-derived structures, in the size range tetra-pentapeptides, were shown to be absorbed in the reverse order of their log P values, to be weakly metabolized in the first hepatic transit and to maintain high blood levels during the observation time. These interesting results obtained by a simple and convenient UV assay, stress once again the importance of monitoring oral absorption early in the process of peptide drug design.