RESUMEN
BACKGROUND: Elevated plasma levels of endothelin (ET)-1 have been reported in association with heart diseases, including heart failure. Furthermore, it has been suggested that ET-1 acts as a local autocrine/paracrine factor with biological activities such as vasoconstriction, mitogenesis, and inotropic effects on the heart. This study investigated alterations of ET-1, ET receptor, and endothelin-converting enzyme (ECE) expression in left ventricular myocardium from patients with end-stage heart failure. METHODS AND RESULTS: mRNA concentrations of ETA and ETB receptors, prepro-ET-1 (ppET-1), and ECE in left ventricles from nonfailing donors hearts (NF) and from patients with end-stage chronic heart failure (NYHA functional class IV) due to dilated cardiomyopathy (DCM) were compared by use of a competitive reverse transcription-polymerase chain reaction technique. There was no significant difference in mRNA expression for ppET-1, ECE-1, and ETA receptors, whereas a significant reduction of ETB-receptor mRNA was observed in DCM hearts. 125I-labeled ET-1 radioligand binding studies demonstrated a significant downregulation of ETB receptors, whereas ETA-receptor density was increased in membranes from DCM hearts. Phosphoramidon-sensitive ECE activity and immunodetectable amounts of ECE protein in left ventricular membrane preparations did not differ between NF and DCM hearts. Finally, immunoreactive ET-1 concentrations were increased in DCM hearts. CONCLUSIONS: The present study demonstrates changes in the ET-receptor expression pattern in favor of the ETA receptor in human end-stage heart failure. Furthermore, activation of the cardiac ET system with increased tissue ET-1 concentrations in the failing myocardium is observed. This is more likely due to decreased clearance than to increased synthesis, because ppET-1 gene expression and ECE activity are unchanged.
Asunto(s)
Ácido Aspártico Endopeptidasas/genética , Endotelina-1/genética , Insuficiencia Cardíaca/genética , Miocardio/metabolismo , Receptores de Endotelina/genética , Transcripción Genética , Factor Natriurético Atrial/genética , Cartilla de ADN , Regulación hacia Abajo , Endotelina-1/metabolismo , Enzimas Convertidoras de Endotelina , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón , Humanos , Metaloendopeptidasas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ensayo de Unión Radioligante , Receptor de Endotelina A , Receptor de Endotelina B , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Receptores de Endotelina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The case of a woman with thrombotic thrombocytopenic purpura refractory to prolonged treatment with plasma exchange and steroid treatment is described. The addition of vincristine yielded a complete response, which has been maintained for 9 months up to the time of this report.
Asunto(s)
Plaquetas/efectos de los fármacos , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Vincristina/uso terapéutico , Femenino , Hemoglobinas/efectos de los fármacos , Humanos , Persona de Mediana Edad , Intercambio Plasmático , Púrpura Trombocitopénica Trombótica/terapia , Resultado del TratamientoRESUMEN
In transgenic rats harboring the mouse Ren-2d gene [TG(mREN2)27], downregulation of the myocardial beta-adrenergic receptor adenylyl cyclase system has been demonstrated previously. Because a reduced vasodilatory reactivity may significantly contribute to hypertension in this model of an activated tissue renin-angiotensin system, the present study investigated alterations of the vascular beta-adrenergic receptor adenylyl cyclase system. In freshly harvested aortas from transgenic rats, the activity of adenylyl cyclase was reduced significantly (P<.05) in the presence of isoprenaline (10 micromol/L; -28+/-4.5%), guanosine 5'-triphosphate, 5'-guanylylimidodiphosphate [Gpp(NH)p] (100 micromol/L; -29+/-4.7%), and forskolin (100 micromol/L) with (-42+/-6%) and without (-40+/-4.3%) MnCl2. Densities of beta-adrenoceptors were similar in both strains. In situ hybridization demonstrated the expression of the transgene in aortic smooth muscle cells. These data indicate a reduced catalyst function as a major contributing factor involved in the maintenance of high blood pressure in TG(mREN2)27. However, in cultivated aortic smooth muscle cells, cAMP production after stimulation with isoprenaline, forskolin, and Gpp(NH)p in the presence or absence of MnCl2 was not different. Affinities and densities of beta-adrenoceptors and amounts of immunochemically detected inhibitory and stimulatory G-protein alpha-subunits were unchanged. Desensitization after incubation with 10 micromol/L isoprenaline for 72 hours was identical in smooth muscle cells from both strains. Cell cultivation and isoprenaline treatment had no effect on transgene expression. We concluded that in transgenic rats the downregulation of the aortic beta-adrenergic adenylyl cyclase system is due to humoral and hemodynamic factors present in vivo rather than to transgenicity itself.
Asunto(s)
Adenilil Ciclasas/metabolismo , Aorta/fisiopatología , Hipertensión/genética , Hipertensión/fisiopatología , Receptores Adrenérgicos beta/metabolismo , Renina/genética , Transducción de Señal , Animales , Animales Modificados Genéticamente , Aorta/metabolismo , Regulación hacia Abajo , Hipertensión/metabolismo , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética , VasodilataciónRESUMEN
1. The aim of the present study was to evaluate the effects of 17 beta-oestradiol in human myocardium. The effects of 17 beta-oestradiol, progesterone and testosterone on force of contraction were investigated in electrically driven isolated atrial trabeculae and ventricular papillary muscles from human hearts in the presence and absence of Bay K 8644, a calcium channel agonist. In addition, the effects of 17 beta-oestradiol, progesterone and testosterone on binding of [3H]-PN 200 110 were assessed in membranes prepared from human ventricular myocardium. 2. 17 beta-Oestradiol elicited a negative inotropic effect in atrial (IC50: 7.1 mumol 1(-1), confidence interval 3.8 to 13.4, n = 3) and ventricular preparations (IC50: 4.6 mumol 1(-1)), confidence interval 2.2 to 9.4, n = 3) as compared with solvent controls. There was no significant difference (P > 0.05) of IC50 values in the absence and presence of isoprenaline (0.0 mumol 1(-1)) in atrial (IC50: 10.8 mumol 1(-1), confidence interval 9.1 to 12.9, n = 6) and ventricular preparations (IC50: 9.4 mumol 1(-1), confidence interval 7.3 to 11.9, n = 8). 3. 17 beta-Oestradiol at 30 mumol 1(-1) induced a significant rightward shift of the concentration-response curves for the positive inotropic effect of Bay K 8644 in atrial preparations (EC50: 0.13 mumol 1(-1), confidence interval 0.08 to 0.19, n = 6; EC50 with 17 beta-oestradiol: 0.58 mumol 1(-1), confidence interval 0.33 to 0.83, n = 6, P < 0.05) and ventricular preparations (EC50: 0.07 mumol 1(-1), confidence interval 0.04 to 0.11, n = 8; EC50 with 17 beta-oestradiol: 0.3 mumol 1(-1), confidence interval 0.18 to 0.49, n = 8, P < 0.05). Testosterone, progesterone at 30 mumol 1(-1) and the solvent control had no significant effect on the concentration-response curves to Bay K 8644. 4. In membranes prepared from human ventricular myocardium the effect of 17 beta-oestradiol on binding of [3H]-PN 200 110, an antagonist at the 1,4 dihydropyridine binding site, was not different from that observed with progesterone, testosterone or solvent controls. 5. In myocardial membranes no specific oestrogen receptors were demonstrated by [3H]-oestradiol binding studies. 6. Thus, the calcium antagonistic property of 17 beta-oestradiol cannot be attributed to a direct interaction with 1, 4 dihydropyridine binding sites.
Asunto(s)
Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Agonistas de los Canales de Calcio/farmacología , Estradiol/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/metabolismo , Membrana Celular/metabolismo , Depresión Química , Estradiol/análisis , Atrios Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Técnicas In Vitro , Isradipino/farmacología , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Progesterona/farmacología , Unión Proteica/efectos de los fármacos , Ensayo de Unión RadioliganteRESUMEN
A 44-year-old German fell ill in Libya, where he had been living for 10 years, with high fever, rigor and a nonitching centrifugally spreading macular rash, which had spared the head, hands and soles. In addition, a systolic cardiac murmur was heard. The Weil-Felix reaction had a titre rising within 3 days from 1:160 to 1:640, confirming the diagnosis of rickettsial disease, the total clinical picture indicating typhus. On treatment with chloramphenicol (1 g three times daily i.v.) the fever subsided within 5 days. On the ninth day treatment was changed to oral doxycyclin, 200 mg daily for 3 weeks. Echocardiography surprisingly revealed a floating thrombus, about 4 x 8 cm, attached to the hypo- and even akinetic apex of the left ventricle. In addition there was single-vessel coronary disease. Since the segmental contraction abnormality persisted after the typhus had been cured, a causal connection with the rickettsial disease is unlikely. The thrombus was removed at the time of a aortocoronary bypass operation: his course has been unremarkable since then.
Asunto(s)
Enfermedad Coronaria/diagnóstico , Cardiopatías/diagnóstico , Trombosis/diagnóstico , Tifus Epidémico Transmitido por Piojos/diagnóstico , Adulto , Terapia Combinada , Enfermedad Coronaria/terapia , Diagnóstico Diferencial , Quimioterapia Combinada , Exantema/diagnóstico , Exantema/tratamiento farmacológico , Alemania/etnología , Cardiopatías/terapia , Ventrículos Cardíacos , Humanos , Libia , Masculino , Trombosis/terapia , Tifus Epidémico Transmitido por Piojos/tratamiento farmacológicoRESUMEN
Pharmacokinetic and pharmacodynamic effects of single oral doses of 200 mg of two atenolol formulations (Tenormin, atenolol (T) and Duraatenolol, atenolol (D)) were assessed in eight male healthy volunteers for 48 h (double-blind crossover design). Both formulations were bioequivalent in terms of pharmacokinetic parameters (AUC, tmax, Cmax, t1/2) as detected by gas liquid chromatography. By means of a radioreceptor assay (RRA) any significant contribution of beta 2-adrenoceptors and active metabolites to effects observed in vivo was ruled out. Based on parameters derived from RRA a prediction of the time course of any beta 1-adrenoceptor-mediated effect in vivo was made. During the first 12 h after intake of atenolol (T) and atenolol (D) effect kinetics simulated from RRA data corresponded very well to the inhibition of exercise-induced tachycardia observed in vivo. Thus, RRA is an in vitro method enabling assessment and prediction of relative bioequivalence of 2 atenolol formulations in vivo. Moreover, it enables establishment of a causal relationship between pharmacodynamic and pharmacokinetic parameters.