RESUMEN
BACKGROUND: The risk of early stroke recurrence amongst patients with symptomatic carotid near-occlusion with and without full collapse is unknown. Therefore, the aim of this study was to analyse the 90-day risk of recurrent ipsilateral ischaemic stroke in patients with symptomatic carotid near-occlusion both with and without full collapse. METHODS: This study was a secondary analysis of the Additional Neurological SYmptoms before Surgery of the Carotid Arteries: a Prospective study (ANSYSCAP). We prospectively analysed 230 consecutive patients with symptomatic 50-99% carotid stenosis or near-occlusion. Based on the combination of several imaging modalities, 205 (89%) patients were classified as having 50-99% carotid stenosis, and 10 (4%) and 15 (7%) as having near-occlusion with and without full collapse, respectively. The 90-day risk of recurrent ipsilateral ischaemic stroke was compared between these three groups. Only events that occurred before carotid endarterectomy were analysed. RESULTS: The 90-day risk of recurrent stroke was 18% [95% confidence interval (CI) 12-25%; n = 29] for patients with 50-99% carotid stenosis, 0% for patients with near-occlusion without full collapse and 43% (95% CI 25-89%; n = 4) for patients with near-occlusion with full collapse (P = 0.035, log-rank test). The increased risk of recurrent ipsilateral ischaemic stroke for patients with symptomatic near-occlusion with full collapse remained significant after multivariable adjustment for age, sex and type of presenting event. CONCLUSIONS: Patients with symptomatic carotid near-occlusion with full collapse might have a very high risk of stroke recurrence. Carotid endarterectomy could be considered for these patients.
Asunto(s)
Arteria Carótida Interna , Estenosis Carotídea/complicaciones , Accidente Cerebrovascular/etiología , Anciano , Estenosis Carotídea/diagnóstico por imagen , Femenino , Humanos , Masculino , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico por imagen , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The PML protein was first identified as part of a fusion product with the retinoic acid receptor alpha (RAR alpha), resulting from the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL). It has been previously demonstrated that PML, which is tightly bound to the nuclear matrix, concentrates in discrete subnuclear compartments that are disorganized in APL cells due to the expression of the PML-RAR alpha hybrid. Here we report that adenovirus infection causes a drastic redistribution of PML from spherical nuclear bodies into fibrous structures. The product encoded by adenovirus E4-ORF3 is shown to be responsible for this reorganization and to colocalize with PML into these fibers. In addition, we demonstrate that E1A oncoproteins concentrate in the PML domains, both in infected and transiently transfected cells, and that this association requires the conserved amino acid motif (D)LXCXE, common to all viral oncoproteins that bind pRB or the related p107 and p130 proteins. The SV-40 large T antigen, another member of this oncoprotein family is also found in close association with the PML nuclear bodies. Taken together, the present data indicate that the subnuclear domains containing PML represent a preferential target for DNA tumor viruses, and therefore suggest a more general involvement of the PML nuclear bodies in oncogenic processes.
Asunto(s)
Proteínas E1A de Adenovirus/metabolismo , Proteínas E4 de Adenovirus/metabolismo , Proteínas de Neoplasias , Matriz Nuclear/metabolismo , Proteínas Nucleares , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Antígenos Transformadores de Poliomavirus/metabolismo , Adhesión Bacteriana , Proteínas Bacterianas , Células HeLa/metabolismo , Células HeLa/ultraestructura , Células HeLa/virología , Humanos , Microscopía Electrónica , Datos de Secuencia Molecular , Proteínas Oncogénicas/metabolismo , Sistemas de Lectura Abierta , Proteína de la Leucemia Promielocítica , Proteínas Supresoras de TumorRESUMEN
Tesaglitazar (GALIDA; AstraZeneca, Wilmington, DE) is a dual peroxisome proliferator-activated receptor alpha/gamma agonist previously in clinical development for the treatment of glucose and lipid abnormalities associated with type 2 diabetes mellitus and insulin resistance. This study compared the efficacy of tesaglitazar with that of pioglitazone as adjunctive therapy to atorvastatin in subjects with abdominal obesity and dyslipidemia. In this open-label, 3-way crossover study, 58 subjects received atorvastatin 10 mg once daily in a 6-week run-in period, followed by tesaglitazar 3 mg, pioglitazone 45 mg, or placebo, as adjunctive therapy to atorvastatin, in a randomized sequence for 6 weeks each. Serum triglycerides and other lipids, apolipoproteins, glucose, and insulin concentrations were compared between treatments. Tesaglitazar adjunctive therapy reduced serum triglycerides significantly more from baseline (-1.07 mmol/L) than pioglitazone (-0.33 mmol/L; P = .007) or placebo (-0.09 mmol/L; P < .0001). Tesaglitazar also resulted in significantly greater improvements in free fatty acids, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio, low-density lipoprotein particle size, apolipoprotein (apo) B, apo C-III, and the apo B/apo A-I ratio compared with pioglitazone or placebo. Tesaglitazar adjunctive therapy also reduced fasting plasma glucose, fasting plasma insulin, and insulin resistance (homeostasis model assessment index) significantly more than pioglitazone or placebo (P < .0001 for all comparisons). Tesaglitazar was generally well tolerated in combination with atorvastatin, but hemoglobin and absolute neutrophil count decreased and serum creatinine increased more with tesaglitazar than with pioglitazone or placebo. These effects, also shown in previous trials, led to the discontinuation of the clinical development of the drug. In conclusion, the addition of tesaglitazar to a background of atorvastatin therapy further improved the dyslipidemia associated with insulin resistance.
Asunto(s)
Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/farmacología , Dislipidemias/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Lípidos/sangre , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/administración & dosificación , Fenilpropionatos/farmacología , Pirroles/uso terapéutico , Adulto , Anticolesterolemiantes/uso terapéutico , Atorvastatina , Quimioterapia Adyuvante , Estudios Cruzados , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Persona de Mediana Edad , Pioglitazona , Placebos , Tiazolidinedionas/administración & dosificaciónRESUMEN
All mRNAs expressed from the adenovirus major late transcription unit have a common, 201-nucleotide-long 5' leader sequence, which consists of three short exons (the tripartite leader). This leader has two variants, either with or without the i-leader exon, which, when present, is spliced between the second and the third exons of the tripartite leader. Previous studies have shown that adenovirus early region 4 (E4) encodes two proteins, E4 open reading frame 3 (E4-ORF3) and E4-ORF6, which are required for efficient expression of mRNAs from the major late transcription unit. These two E4 proteins appear to have redundant activities, and expression of one has been shown to be sufficient for efficient major late mRNA accumulation during a lytic virus infection. In this report, we provide evidence that E4-ORF3 and E4-ORF6 both regulate major late mRNA accumulation by stimulating constitutive splicing. Moreover, we show that the two proteins have different effects on accumulation of alternatively spliced tripartite leader exons. In a DNA transfection assay, E4-ORF3 was shown to facilitate i-leader exon inclusion, while E4-ORF6 preferentially favored i-leader exon skipping. In addition, E4-ORF3 and E4-ORF6 had the same effects on accumulation of alternatively spliced chimeric beta-globin transcripts. This finding suggests that the activities of the two proteins may be of more general relevance and not restricted to splicing of major late tripartite leader-containing pre-mRNAs. Interestingly, E4-ORF6 expression was also shown to stimulate i-leader exon skipping during a lytic virus infection.
Asunto(s)
Adenovirus Humanos/genética , Adenovirus Humanos/metabolismo , Empalme Alternativo , ARN Mensajero/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismo , Secuencia de Bases , Cartilla de ADN/genética , ADN Viral/genética , Exones , Células HeLa , Humanos , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Mensajero/genética , Transcripción GenéticaRESUMEN
Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.
Asunto(s)
Alcanosulfonatos/farmacocinética , Alimentos , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/farmacocinética , Adulto , Alcanosulfonatos/efectos adversos , Alcanosulfonatos/sangre , Salud , Humanos , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversos , Fenilpropionatos/sangreRESUMEN
OBJECTIVE: To compare the relationships of treatment-induced reductions of left ventricular hypertrophy to the changes in clinic and ambulatory blood pressure (BP). DESIGN: Double-blind and randomized treatment with irbesartan or atenolol for 48 weeks. PATIENTS: Patients with hypertension and left ventricular hypertrophy (n = 66) with a seated diastolic BP 90-115 mmHg (average of three measurements one minute apart by nurses). MAIN OUTCOME MEASURES: Registrations of echocardiographic left ventricular (LV) mass. Clinic and ambulatory BP. RESULTS: In the total material, nurse-measured BP was reduced by 23 +/- 15/16 +/- 7.7 mmHg and 24-h ambulatory BP fell 20 +/- 15/14 +/- 8.5 mmHg by treatment. The correlation between the change in nurse-measured BP and LV mass index (LVMI) induced by treatment was r = 0.35, P = 0.004 for systolic BP and r = 0.26, P = 0.03 for diastolic BP. Corresponding values for 24-h ambulatory BP were r = 0.29, P = 0.02 and r = 0.35, P = 0.004, respectively, with similar correlations for day- and night-time ambulatory BP. The nurse-recorded BP was slightly higher than ambulatory BP (systolic clinic - systolic 24-h ambulatory BP = 5 mmHg). Using 130/80 mmHg as a cut-off value for normal 24-h ambulatory BP, eight subjects had normal diastolic or systolic ambulatory BP, or both. Interestingly, these patients also experienced LVMI regression following treatment (low/normal ABP, -13 +/- 21 g/m2; remaining patients, -18 +/- 22 g/m2, P > 0.5). CONCLUSIONS: In patients with hypertension and left ventricular hypertrophy, ambulatory BP is not superior to carefully standardized nurse-recorded seated BP in terms of associations with treatment-induced changes in LV mass.
Asunto(s)
Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Tetrazoles/uso terapéutico , Adulto , Presión Sanguínea/efectos de los fármacos , Determinación de la Presión Sanguínea/enfermería , Monitoreo Ambulatorio de la Presión Arterial , Método Doble Ciego , Ecocardiografía , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Irbesartán , Masculino , Persona de Mediana Edad , Pronóstico , SueciaRESUMEN
OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/fisiología , Tetrazoles/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Atenolol/uso terapéutico , Método Doble Ciego , Femenino , Predicción , Humanos , Irbesartán , Masculino , Persona de Mediana Edad , Receptor de Angiotensina Tipo 1 , Resultado del TratamientoRESUMEN
BACKGROUND: The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1(wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated. OBJECTIVE: To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan. DESIGN AND METHODS: One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing. RESULTS: The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/CYP2C9*2 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9. CONCLUSIONS: The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.
Asunto(s)
Antihipertensivos/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/efectos de los fármacos , Hidrocarburo de Aril Hidroxilasas/genética , Compuestos de Bifenilo/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Tetrazoles/uso terapéutico , Adulto , Anciano , Antihipertensivos/administración & dosificación , Atenolol/administración & dosificación , Atenolol/uso terapéutico , Compuestos de Bifenilo/administración & dosificación , Citocromo P-450 CYP2C9 , Diástole/efectos de los fármacos , Diástole/genética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Evaluación de Medicamentos , Femenino , Genotipo , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/fisiopatología , Irbesartán , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Suecia , Sístole/efectos de los fármacos , Sístole/genética , Tetrazoles/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.
Asunto(s)
Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/genética , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/genética , Receptor de Bradiquinina B2/genética , Tetrazoles/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Método Doble Ciego , Femenino , Genotipo , Humanos , Hipertensión/patología , Hipertrofia Ventricular Izquierda/patología , Irbesartán , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Polimorfismo Genético , SueciaRESUMEN
BACKGROUND: The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA). OBJECTIVE: Angiotensin II induces myocardial hypertrophy. We hypothesized that blockade of angiotensin II subtype 1 (AT1) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass (as measured by echocardiography) more than conventional treatment with a beta blocker. DESIGN AND METHODS: This double-blind study randomized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d. or atenolol 50 mg q.d. for 48 weeks. If diastolic blood pressure remained above 90 mmHg, doses were doubled, and additional medications (hydrochlorothiazide and felodipine) were prescribed as needed. Echocardiography was performed at weeks 0, 12, 24 and 48. RESULTS: Baseline mean blood pressure was 162/ 104 mmHg, and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women. Systolic and diastolic blood pressure reductions were similar in both treatment groups. Both irbesartan (P < 0.001) and atenolol (P< 0.001) progressively reduced left ventricular mass index, e.g. by 26 and 14 g/m2 (16 and 9%), respectively, at week 48, with a greater reduction in the irbesartan group (P = 0.024). The proportion of patients who attained a normalized left ventricular mass (i.e. < or = 131 g/m2 for men and < or = 100 g/m2 for women) tended to be greater with irbesartan (47 versus 32%, P = 0.108). CONCLUSIONS: Left ventricular mass was reduced more in the irbesartan group than in the atenolol group. These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism, beyond that of lowering blood pressure, in the regulation of left ventricular mass and geometry in patients with hypertension.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Tetrazoles/uso terapéutico , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Atenolol/efectos adversos , Atenolol/uso terapéutico , Compuestos de Bifenilo/efectos adversos , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/complicaciones , Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Irbesartán , Masculino , Persona de Mediana Edad , Receptor de Angiotensina Tipo 1 , Seguridad , Tetrazoles/efectos adversos , Resistencia Vascular/efectos de los fármacosRESUMEN
The immediate (0 to 24 hours) and long-term (4 weeks) hypotensive effects of a new long-acting angiotensin converting enzyme inhibitor, ramipril (HOE 498), as well as adverse effects and tolerance, were evaluated in 34 patients with primary hypertension. Further, effects on serum and urinary aldosterone and circulating angiotensin II concentrations were measured. After short- and long-term administration of 5 or 10 mg of ramipril, the mean blood pressure was significantly lowered compared with placebo. The mean maximum decrease in blood pressure was noted 4 to 8 hours after administration of ramipril once daily. Sustained blood pressure reduction was achieved after 4 weeks of treatment. Serum concentrations of aldosterone and plasma levels of circulating angiotensin II were reduced for up to 12 hours after drug intake, and tended to return to pretreatment levels at 24 hours. Serum angiotensin converting enzyme activity was markedly suppressed for more than 24 hours after a single dose of 5 or 10 mg ramipril. No subjective or objective adverse effects were noted, and the tolerance to the drug was very good.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos con Puentes/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Administración Oral , Adulto , Anciano , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/efectos adversos , Femenino , Humanos , Hipertensión/sangre , Masculino , Persona de Mediana Edad , Postura , RamiprilRESUMEN
We show that transformation of rat CREF fibroblasts by adenovirus-2 early regions 1A and 1B (E1) is stimulated by expression of the viral early region 4 (E4) products. Cotransfection of CREF cells with E1 and E4 did not affect the number of E1-transformed foci, but resulted in the formation of larger and more dense foci compared to E1 transfection alone. Cells obtained from these foci were capable of anchorage-independent growth. The adenovirus-2 E4 region encodes for a minimum of seven proteins, several of which have been shown to have distinct biological activities. To assay for the activity of these individual proteins on E1 transformation, we used expression vectors designed to encode single E4 proteins in the CREF cell transformation assay. By this strategy, we could show that two E4 proteins had a significant capacity to stimulate E1 transformation. Cotransfection of E1 and vectors encoding the E4-ORF1 or E4-ORF6 proteins resulted in the formation of large dense foci typical of E4-cotransformed cells. However, no single E4-ORF-expressing plasmid was sufficient to reproduce the stimulative effect on CREF cell transformation observed using the entire E4 region.
RESUMEN
Amlodipine and felodipine are calcium antagonists of the dihydropyridine type. The elimination half-life of amlodipine is longer than that of felodipine. To study whether the different elimination rates of the drugs were reflected in different duration of blood pressure (BP) control, we compared amlodipine and felodipine extended release (ER) by both conventional clinic BP 24 h after drug intake and 24 h ambulatory BP monitoring (ABPM), with special reference to nighttime and morning blood pressure. Two hundred and sixteen patients with primary hypertension (supine diastolic BP, 95 to 115 mm Hg) were randomized to receive amlodipine or felodipine ER in a multicenter study. The starting dose of both drugs was 5 mg. If the target clinic diastolic BP (90 mm Hg) had not been achieved after 4 weeks the dose was increased to 10 mg. Twenty-four-hour ABPM was performed with the subjects taking placebo medication before randomization and after 4 and 8 weeks undergoing active treatment. Significantly more patients responded after 4 weeks of treatment with amlodipine (50%) as compared with felodipine (33%) (P = .013). ABPM during daytime (07:00 to 23:00) was similar during both treatments, but nighttime systolic (P = .026) and diastolic (P = .019) BP was more effectively reduced by amlodipine than by felodipine. After 8 weeks 82% achieved the target pressure with amlodipine and 69% with felodipine (P = .036 for the difference). Amlodipine seems to be more effective than felodipine when the drugs are compared in the same dose, with regard to the effect on clinic BP 24 h after dosing and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding.
Asunto(s)
Amlodipino/administración & dosificación , Amlodipino/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacocinética , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/farmacocinética , Felodipino/administración & dosificación , Felodipino/farmacocinética , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Monitoreo Ambulatorio de la Presión Arterial , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The regional hemodynamic effects of endothelin-1 (ET-1) were studied in Wistar-Kyoto rats. Endothelin-1 caused a transient increase in blood flow in the carotid and femoral arteries but a decrease in flow in the renal and mesenteric arteries. The resistance in the carotid and femoral beds decreased while it increased in the renal and mesenteric beds. Subsequently there was a variable increase in resistance in all vascular beds with a maximal increase in the renal bed. Thus, ET-1 initially causes a selective vasorelaxation in musculocutaneous beds but not in visceral beds; the cause of this selectivity is unknown.
Asunto(s)
Arterias Carótidas/efectos de los fármacos , Endotelinas/farmacología , Arteria Femoral/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Arteria Renal/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Animales , Arterias Carótidas/fisiología , Evaluación Preclínica de Medicamentos , Arteria Femoral/fisiología , Masculino , Arterias Mesentéricas/fisiología , Ratas , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/efectos de los fármacos , Arteria Renal/fisiología , Factores de Tiempo , Resistencia Vascular/efectos de los fármacosRESUMEN
Ultrasound-Doppler assessment of diastolic function is subject to velocity errors caused by angle sensitivity and a fixed location of the sample volume. We used 3-dimensional phase contrast magnetic resonance imaging (MRI) to evaluate these errors in 10 patients with hypertension and in 10 healthy volunteers. The single (Doppler) and triple (MRI) component velocity was measured at early (E) and late (A) inflow along Doppler-like sample lines or 3-dimensional particle traces generated from the MRI data. Doppler measurements underestimated MRI velocities by 9.4% +/- 8.6%; the effect on the E/A ratio was larger and more variable. Measuring early and late diastolic inflows from a single line demonstrated the error caused by their 3-dimensional spatial offset. Both errors were minimized by calculating the E/A ratio from maximal E and A values without constraint to a single line. Alignment and spatial offset are important sources of error in Doppler diastolic parameters. Improved accuracy may be achieved with the use of maximal E and A velocities from wherever they occur in the left ventricle.
Asunto(s)
Diástole/fisiología , Ecocardiografía Doppler en Color , Hipertensión/fisiopatología , Imagen por Resonancia Magnética , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Contracción MiocárdicaRESUMEN
A population-based study was performed in order to study the interrelationships of the circulating components of the renin-angiotensin system during basal conditions and their relations to blood pressure (BP), age and gender. One hundred and four women and 95 men, 16-70 years old, evenly age distributed and randomly selected from the population of Linköping, Sweden, participated. Venous blood was drawn at 08.00 hours and ambulatory BP recording was then performed. Serum angiotensin-converting enzyme (ACE) activity correlated with plasma angiotensin II (r = 0.20, P = 0.004), but when calculated separately according to gender, the correlation remained significant only in men (r = 0.33, P = 0.001). Plasma renin activity (PRA) correlated negatively with age (r = -0.30, P < 0.0001), but immunoreactive active renin (IRR) and angiotensin II did not. PRA and IRR correlated negatively with BP in women but correlations disappeared after age adjustment. The 23 women on oestrogen medication did not differ from the remaining 81 with respect to age (P = 0.5), IRR (P = 0.96) or angiotensin II (P = 0.4) levels, but PRA was higher (2.2 +/- 1.4 ng Ang l/ml/h and 1.5 +/- 0.9 ng Ang l/ml/h, respectively, P = 0.004). PRA (r = 0.38, P < 0.0001) and IRR (r = 0.49, P < 0.0001) correlated positively with the levels of angiotensin II. In conclusion the fact that PRA, but not IRR, declined with age and was higher among oestrogen-treated women, although angiotensin II was unaffected suggests IRR to be a more robust marker of angiotensin II levels than is PRA in a population-based setting. ACE correlates positively with angiotensin II in men.
Asunto(s)
Angiotensina II/sangre , Presión Sanguínea , Peptidil-Dipeptidasa A/sangre , Sistema Renina-Angiotensina/fisiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , SueciaRESUMEN
The systemic and regional hemodynamic effects of endothelin (ET), a novel endothelial derived vasoconstrictor peptide were studied in Wistar Kyoto rats. A bolus of 1 nmol/Kg ET intravenously induced a transient 43% decrease in blood pressure associated with a 57% decrease in systemic resistance and a 30% increase in cardiac output (p less than 0.01 for all parameters). This was followed by an increase of 20% in arterial pressure and of 71% in systemic resistance and a decrease of 30% in cardiac output at 10 minutes. The initial fall in blood pressure was not abolished by pretreatment with verapamil, captopril, indomethacin, ketanserin, atropine, methylene blue or ethanol. Verapamil abolished the hypertensive phase by markedly decreasing cardiac output. ET had selective effects on the arterial tree; during the hypotensive phase it caused a transient increase in blood flow in the carotid and femoral arteries (+41% and +83% respectively, p less than 0.01) but a decrease in flow in the renal and mesenteric arteries (-53% and -44% respectively, p less than 0.05). Accordingly, there was a decrease in resistance in the carotid and femoral beds (-55% and -67% respectively, p less than 0.01) and an increase in resistance in the renal and mesenteric beds (+102%; p less than 0.01 and +23%; p = N.S. respectively). Subsequently there was an increase in resistance in all vascular beds to variable degrees. The maximal increase in resistance was in the renal bed (+156%). Thus, ET causes initially a potent systemic vasorelaxation and an increase in cardiac output later progressing to systemic vasoconstriction and a decrease in cardiac output. The initial vasodilation is selective, appearing in musculocutaneous beds but not in visceral beds.
Asunto(s)
Gasto Cardíaco/efectos de los fármacos , Endotelio Vascular/fisiología , Hemodinámica/efectos de los fármacos , Péptidos/farmacología , Vasodilatación/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Endotelinas , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
The efficacy and tolerability of the new ACE-inhibitor enlalapril (MK 421) and the beta 1-selective adrenoceptor blocker atenolol for the treatment of primary hypertension were compared in a double blind parallel study. 12 patients were randomized to each drug. The doses of enalapril were 20 and 40 mg o.d and of atenolol 50 and 100 mg o.d. for 4 weeks each, whereafter hydrochlorothiazide (HCTZ) 25 or 50 mg o.d. was added if necessary to achieve a supine diastolic blood pressure (BP) <90 mm Hg 24 hours after drug intake. Supine BP was reduced from 160±7/111±4 mm Hg to 153±13/101±9 mm Hg (p<0.05/p<0.005) with enalapril and from 163±17/109±6 mm Hg to 145±11/95±7 mm Hg (p<0.005/p<0.001) with atenolol. The addition of HCTZ caused a profound additive BP reduction to 132±7/88±6 mm Hg with enalapril and to 130±10/88±7 mm Hg with atenolol. There was no significant difference between the efficacy of enalapril and atenolol alone or combined with HTCZ. The reduction in mean arterial pressure with enalapril tended to correlate with pre-treatment stimulated plasma renin activity and 24 hours urinary kallikrein excretion. Both drugs tended to reduce serum and urinary aldosterone and kallikrein excretion to the same extent. There was one drop-out in each group, one due to impotence on the combination of enalapril and HCTZ and one due to peripheral coldness during atenolol treatment. Other side effects were mild. No toxic adverse effects were registered.
RESUMEN
We assessed the antihypertensive and hormonal effects of two new angiotensin converting enzyme (ACE) inhibitors. enalapril (MK-421) and lisinopril (MK-521) in 22 patients with renovascular hypertension. All patients had angiographically verified renal artery lesions, 3 had bilateral renal artery stenosis and one a stenosis in a single kidney, and the rest had unilateral renal artery stenosis. After placebo treatment for 3 days in hospital, increasing doses from 5 to 40 mg daily, of both ACE-inhibitors were given. Both drugs induced a significant fall in blood pressure (BP). Significant BP reductions were seen after 2 h with a maximum fall for the enalapril group at a dose of 40 mg 4 h after drug intake (mean supine BP decrease-31/24 mm Hg, standing-29/16 mmHg). The corresponding maximal BP reductions were for the lisinopril group at a dose of 40 mg o.d. at 6 h: mean supine BP fall-25/28 mmHg and standing-33/31 mm Hg. Both drugs significantly inhibited serum ACE to about 5 to 10% of initial values and with a duration for more than 24 h. Both drugs also caused a decrease in plasma All levels and also in plasma aldosterone concentrations. There were no toxic effects and no serious side effects. Careful monitoring of biochemical variables showed no significant changes. We conclude that both enalapril and lisinopril are effective and very Safe agents for the treatment of renovascular hypertension and with a long duration of action and with very good tolerance.
RESUMEN
BACKGROUND: Studies suggest that the Ser49Gly and Arg389Gly polymorphisms in the beta1-adrenergic receptor might be of functional importance for the cardiovascular system. Both have been associated with altered receptor activity in vitro, and with hypertension and cardiac failure in vivo. HYPOTHESIS: The aim of this study was to test whether these polymorphisms were associated with the change in heart rate or blood pressure in patients with essential hypertension and left ventricular (LV) hypertrophy treated with the beta1-adrenergic receptor blocker atenolol. METHODS: Blood pressure and heart rate were measured in 101 hypertensive patients with echocardiographically verified LV hypertrophy, randomized in a double-blind study to treatment with either the beta1-adrenergic receptor blocker atenolol or the angiotensin II type I receptor antagonist irbesartan. Changes in blood pressure and heart rate were evaluated after 12 weeks. Beta1-adrenergic receptor genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found no significant associations between the changes in the measured variables and either of the two polymorphisms. However, carriers of the 49Gly allele showed a tendency toward a greater reduction in heart rate compared with patients with the Ser/Ser49 genotype (p = 0.06). CONCLUSIONS: The Ser49Gly and Arg389Gly beta1-adrenergic receptor polymorphisms do not seem to exert a major effect on the changes in heart rate and blood pressure during 12 weeks of treatment with atenolol in patients with essential hypertension and LV hypertrophy.