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AIM: To review and describe commonly encountered artefacts in contrast-enhanced spectral mammography (CESM). MATERIALS & METHODS: This retrospective study included 200 women who underwent CESM examinations for screening and diagnostic purposes. Analysis was performed on the image data sets of these women, comprising of a total of 774 subtracted images. Images were reviewed with focus on the presence of four artefacts: rim ("breast within breast"), ripple (black and white lines), axillary line, and skin-line enhancement (skin-line highlighting). Statistical cross-correlation and association with acquisition parameters (tube current, tube voltage, compression force, breast thickness, paddle size) was compared using Fisher's exact test and t-test. RESULTS: The rim artefact was highly common (97-99%) in every projection. The ripple artefact was increasingly more common on the oblique projections (80-82%) and found to be associated with higher breast thickness values. The axillary line artefact was detected only on oblique projections (63%) and associated with the use of a small compression paddle. The skin-line enhancement artefact was seen in 19-46% of projections. None of the artefacts interfered with image interpretation. CONCLUSIONS: Two main artefacts commonly seen on CESM are rim and ripple artefacts. They do not hamper with image interpretation. It is important to be aware of them and prevent misinterpretation of these artefacts as real breast pathology.
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Mamografía/métodos , Adulto , Anciano , Artefactos , Femenino , Humanos , Persona de Mediana Edad , Pezones/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
The newly inbred Cohen diabetic rat is an exceptional experimental model of diet-induced type 2 diabetes mellitus that is the result of secondary inbreeding nearly 30 years after it originally had been established. Animals from the original colony were selectively inbred by stringent criteria for 10 additional generations, bringing overall inbreeding to >50 generations. The metabolic phenotypes of the resulting contrasting strains, designated as the Cohen diabetic-sensitive (CDs) and -resistant (CDr) rats, were characterized. The phenotype of the CDs strain that was fed a regular diet consisted of fasting normoglycemia, normal glucose tolerance to intraperitoneal glucose loading, normal fasting insulin levels, and a normal insulin response to glucose loading. In contrast, CDs rats that were fed a custom-prepared high-sucrose low-copper diabetogenic diet became overtly diabetic: fasting glucose levels were normal or elevated, and the blood glucose insulin response to glucose loading was markedly abnormal. CDr rats that were fed a regular or diabetogenic diet did not develop diabetes and maintained normal glucose tolerance and insulin secretion. A striking sex difference was observed in CDs rats that were fed a diabetogenic diet: males had a lower growth rate and a more severe glucose intolerance pattern than females. Gonadectomy shortly after weaning did not prevent the development of the diabetic phenotype in its early phase in either sex but markedly attenuated its expression in males at a later phase, abolishing the sex differences. Alternate-day feeding, as opposed to daily feeding, also attenuated the metabolic phenotype in males. The development of the diabetic phenotype in CDs rats that were fed a diabetogenic diet was not accompanied by obesity or hyperlipidemia. The genetic profile of the strains was established using 550 microsatellite markers evenly distributed throughout the rat genome. The rate of homozygosity within strain was > or = 96%. The rate of polymorphism between the contrasting strains was 43%. We conclude that the metabolic phenotypes of the rebred colony of CDs and CDr rats and their genetic makeup render the Cohen diabetic rat a useful experimental model that is highly suitable for studying the interaction between nutritional-metabolic environmental factors and genetic susceptibility (sensitivity and resistance) for the development of type 2 diabetes. The model is also distinctively useful for investigating the effect of sex on the expression of the diabetic phenotype.
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Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/genética , Dieta , Ratas Endogámicas/genética , Caracteres Sexuales , Animales , Presión Sanguínea , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Genotipo , Prueba de Tolerancia a la Glucosa , Inyecciones Intraperitoneales , Insulina/sangre , Masculino , Fenotipo , Polimorfismo Genético , Ratas , Ratas Endogámicas/crecimiento & desarrollo , Ratas Endogámicas/metabolismoRESUMEN
Unusual serum electrolyte abnormalities developed in eight patients who nearly drowned (ND) in the Dead Sea. Elevations in serum calcium and magnesium levels in particular required specific therapeutic intervention. The Dead Sea has a uniquely high concentration of calcium, magnesium, sodium, potassium, and chloride. The unusual serum electrolyte elevation that was observed in the ND victims in the Dead Sea apparently reflected the large solute load to which they were exposed. Four patients died subsequent to ND. Near drowning in the Dead Sea therefore represents a clinical entity that is associated with a high fatality rate and in which unrecognized major electrolyte abnormalities, in addition to the known respiratory complications, may influence the outcome.
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Ahogamiento/sangre , Electrólitos/sangre , Anciano , Calcio/sangre , Femenino , Humanos , Israel , Magnesio/sangre , Masculino , Persona de Mediana Edad , Agua de MarRESUMEN
Hypertension is one of the major common polygenic and multifactorial diseases, and continues to constitute a major cause of morbidity and mortality worldwide. The pathophysiological mechanisms underlying hypertension have not been elucidated, which significantly limits our ability to treat and prevent hypertension. A frequently asked question is whether genomics will provide the solution to the many remaining unanswered questions as to the causes of hypertension. Genomics, an art by its own virtue, holds its promises, yet the questions we are asking of genomics must be well defined for genomics to meet at least some of our expectations. The hopes and promises of genomics are high and one of the major hopes is that genomics will improve our understanding of the pathophysiology of hypertension and enable us to classify hypertensive syndromes more succinctly and enhance our ability to provide patients with specific anti-hypertensive therapy as well as predict outcome. There is still much to be done but perseverance in the task and a firm belief in genomics and in the immense potential of the human genome is essential.
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Hipertensión/genética , Predisposición Genética a la Enfermedad , Genómica , Humanos , Hipertensión/fisiopatología , Hipertensión/terapiaRESUMEN
The effect of selective glucocorticoid or mineralocorticoid replacement on pressor responses to angiotensin I and II and norepinephrine was studied in adrenalectomized rats given high salt intake. Four groups were prepared by 1) adrenalectomy only (n = 5); 2) adrenalectomy plus aldosterone, 6 micrograms/24 hr i.p. (n = 5); or 3) adrenalectomy plus dexamethasone, 10 micrograms/24 hr i.p. (n = 5), using miniosmotic pumps; and 4) sham adrenalectomy (controls; n = 5). Plasma corticosterone was undetectable in all three adrenalectomized groups. Plasma aldosterone concentration was similar in aldosterone-replaced and sham-operated controls. Pressor responses to various doses of angiotensin I, angiotensin II, and norepinephrine were determined in unanesthetized, undisturbed rats. Compared with both control and dexamethasone-replaced rats, pressor responses to all three agonists were significantly reduced in both nonreplaced adrenalectomized and aldosterone-replaced groups. Comparing the ratios of the pressor responses to angiotensin I and angiotensin II in the four groups over the entire dose range suggests that a greater fraction of injected angiotensin I was converted to angiotensin II in nonreplaced adrenalectomized rats than in the other three groups. We conclude that glucocorticoid action markedly contributes to the systemic pressor effect of angiotensin and norepinephrine. However, glucocorticoid deficiency does not impair in vivo conversion of angiotensin I to angiotensin II.
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Glándulas Suprarrenales/fisiología , Aldosterona/farmacología , Presión Sanguínea/efectos de los fármacos , Dexametasona/farmacología , Presorreceptores/efectos de los fármacos , Adrenalectomía , Angiotensina I/farmacología , Angiotensina II/farmacología , Animales , Estado de Conciencia , Masculino , Norepinefrina/farmacología , Ratas , Ratas EndogámicasRESUMEN
Salt-resistant (SBN/y) and salt-sensitive (SBH/y) Sabra rats are a useful model of salt-sensitive hypertension with incompletely explored renal mechanisms. We investigated their pressure-natriuresis curves, with and without deoxycorticosterone acetate (DOCA)-salt treatment. To differentiate between extrinsic neural and hormonal mechanisms and intrinsic renal influences, we performed experiments with neural denervation, adrenalectomy, and infusions of vasopressin, norepinephrine, 17-hydroxycorticosterone, and aldosterone as well as without these maneuvers. In untreated SBN/y without controlled neural and circulating hormonal factors, urine flow and sodium excretion increased from 32 to 95 microL/min per gram kidney weight (gkwt) and from 4 to 17 mumol/min per gkwt, respectively, as renal perfusion pressure was increased from 85 to 146 mm Hg. Renal blood flow and glomerular filtration rate were autoregulated and averaged 7.5 and 1.2 mL/min per gkwt. In untreated SBN/y with controlled neural and circulating factors, pressure-diuresis and -natriuresis curves were shifted toward the right, and renal blood flow and glomerular filtration rate ranged between 4.2 and 9.1 or 1 and 1.3 mL/min per gkwt as perfusion pressure was increased from 99 to 164 mm Hg. In both protocols, values in SBH/y did not differ. DOCA-salt increased blood pressure in SBH/y. In SBH/y without controlled neural and hormonal factors, pressure-diuresis and -natriuresis curves were shifted approximately 20 mm Hg toward the right. Fractional sodium and water excretion curves, renal blood flow, and glomerular filtration rate were shifted rightward in parallel. On the other hand, SBH/y with DOCA-salt and controlled neural and hormonal factors had lower sodium and water excretion rates only at the renal perfusion pressure of 150 mm Hg as well as decreased renal blood flow and glomerular filtration rate compared with DOCA-salt SBN/y. These data suggest that both extrinsic and intrinsic factors are responsible for reduced sodium and water excretory capacity in DOCA-salt SBH/y; however, the extrinsic factors may be more important.
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Desoxicorticosterona/farmacología , Hipertensión/fisiopatología , Natriuresis/efectos de los fármacos , Sodio/farmacología , Adrenalectomía , Animales , Presión Sanguínea/efectos de los fármacos , Combinación de Medicamentos , Tasa de Filtración Glomerular/efectos de los fármacos , Homeostasis/efectos de los fármacos , Hipertensión/etiología , Riñón/efectos de los fármacos , Masculino , Presión , Ratas , Ratas Endogámicas , Circulación Renal/efectos de los fármacos , Sodio/sangreRESUMEN
The long-term antihypertensive effect of combined nifedipine and propranolol therapy was assessed in an open trial in 26 hypertensive patients (19 men, seven women, mean age 53 years). On propranolol alone (160 to 240 mg/day), the patients' average sitting blood pressure was 192 +/- 5/114 +/- 2 mm Hg. Propranolol was continued in a fixed dose and nifedipine was added in a dose that was gradually increased from 30 to 90 mg/day to achieve blood pressure (BP) values below 160/95 mm Hg. Twenty-two patients remained on the combined regimen for 14 to 30 weeks. Their BP decreased to 136 +/- 3/84 +/- 2 mm Hg on an average daily dose of 59.5 mg nifedipine. Seventeen of the 22 subjects were subsequently treated sequentially with propranolol alone, combined therapy, and nifedipine alone, to assess the relative efficacy of each mode of therapy. The combined regimen was found to be more effective than either drug alone. Side effects occurred in 13 of 26 patients. Four dropped out 4 to 11 weeks after starting nifedipine because of either intolerable flushing (2), allergic rash (1), or headache (1). Nine subjects experienced mild reactions that were well tolerated. It is concluded that the combined use of propranolol and nifedipine is effective in the long-term treatment of moderately severe hypertension and offers an alternative therapeutic approach that deserves further evaluation.
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Hipertensión/tratamiento farmacológico , Nifedipino/administración & dosificación , Propranolol/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nifedipino/efectos adversos , Propranolol/efectos adversos , Factores de TiempoRESUMEN
Random genome screening was initiated in the Sabra rat model of hypertension in search of genes that account for salt sensitivity or salt resistance in terms of the development of hypertension. Female salt-sensitive Sabra hypertension-prone (SBH/y) rats were crossed with male salt-resistant Sabra hypertension-resistant (SBN/y) rats, resulting in an F2 cohort consisting of 100 males and 132 females. Systolic blood pressure (BP) was measured in rats at 6 weeks of age under basal conditions and after 4 weeks of salt loading. Genotypes for 24 polymorphic microsatellite markers localized to chromosome 1 and for 8 markers localized to chromosome 17 were determined in F2 and cosegregation with BP was evaluated by ANOVA and multipoint linkage analysis. Basal BP did not cosegregate with any locus on chromosomes 1 or 17. In contrast, BP after salt loading showed significant cosegregation with three QTLs, two on chromosome 1 and one on chromosome 17, designated SS1a, SS1b, and SS17, respectively; the maximal logarithm of the odds (LOD) scores were 4.71, 4.91, and 3.43, respectively. Further analysis revealed sexual dimorphism. In male F2, BP response to salt loading cosegregated with one QTL (LOD score 4.52) and a second QTL (LOD score 2.98), both on chromosome 1 and coinciding with SS1a and SS1b, respectively. In female rats, BP response cosegregated with one QTL on chromosome 1 (LOD score 3.08) coinciding with SS1b, and with a second QTL on chromosome 17 (LOD score 3.66) coinciding with SS17. In males, the additive effects of the two QTLs on chromosome 1 accounted for most of the BP variance to salt loading, whereas in females the additive effects of the QTLs on chromosomes 1 and 17 accounted for over two thirds of the variance. These results identify three putative gene loci on chromosomes 1 and 17 that contribute importantly to salt sensitivity and/or resistance and uncover sex specificity in the role that salt susceptibility genes fulfill in the development of hypertension.
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Mapeo Cromosómico , Hipertensión/genética , Sodio en la Dieta/farmacología , Análisis de Varianza , Animales , Presión Sanguínea/efectos de los fármacos , Cromosomas/genética , Modelos Animales de Enfermedad , Femenino , Genotipo , Hipertensión/etiología , Hipertensión/fisiopatología , Escala de Lod , Masculino , Repeticiones de Microsatélite , Fenotipo , Carácter Cuantitativo Heredable , Ratas , Ratas Endogámicas , Caracteres SexualesRESUMEN
We carried out a total genome screen in the Sabra rat model of hypertension to detect salt-susceptibility genes. We previously reported in male animals the presence of 2 major quantitative trait loci (QTLs) on chromosome 1 that together accounted for most of the difference in the blood pressure (BP) response to salt loading between Sabra hypertension-prone rats (SBH/y) and Sabra hypertension-resistant rats (SBN/y). In females, we reported on 2 major QTLs on chromosomes 1 and 17 that together accounted for only two thirds of the difference in the BP response between the strains. On the basis of phenotypic patterns of inheritance in reciprocal F2 crosses, we proposed a role of the X chromosome. We therefore continued the search for the missing QTL in females that would account for the remaining difference in the BP response between the 2 strains using newly developed microsatellite markers and focusing on chromosome X. We screened an F2 cross, consisting of 371 females and 336 males, using 19 polymorphic chromosome X microsatellite markers. We analyzed the averages of BP by genotype using ANOVA and the individual data using MAPMAKER/QTL. In female F2 progeny, we identified a segment on chromosome X that spans over 33.4 cM and shows significant cosegregation (P<0.001) of 14 microsatellite markers (demarcated by DXRat4 and DXMgh10) with systolic BP after salt loading. This segment has 2 apparent peaks at DXRat4 and DXRat13, with a BP effect of 14 mm Hg for each. Multipoint linkage analysis with a free model detected 3 peaks (logarithm of the odds ratio [LOD] score >4.3) within the same chromosomal segment: One between DXMgh9 and DXMit4 (LOD 4.9; 6.1% of variance), a second between DXMgh12 and DXRat8 (LOD 5.2; 7.2% of variance), and a third between DXRat2 and DXRat4 (LOD 5.8; 7.5% of variance). On the basis of these findings and until congenic strains become available, our working assumption is that within chromosome X, 1 to 3 genetic loci contribute importantly to the BP response of female Sabra rats to salt. In male F2 progeny, we detected no significant cosegregation of any region on chromosome X with the BP response to salt loading. We conclude that in the female rat, salt susceptibility is mediated by 3 to 5 gene loci on chromosomes 1, 17, and X, whereas in the male rat, the X chromosome does not affect the BP response to salt.
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Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Hipertensión/genética , Cromosoma X , Animales , Cruzamientos Genéticos , Femenino , Ligamiento Genético , Marcadores Genéticos , Genotipo , Israel , Masculino , Repeticiones de Microsatélite , Fenotipo , Polimorfismo Genético , Carácter Cuantitativo Heredable , Ratas , Ratas Endogámicas , Caracteres Sexuales , Sodio en la DietaRESUMEN
The molecular mechanisms of salt sensitivity and the contribution of the kidney to salt-induced hypertension in Sabra rats are imperfectly defined. We investigated the expression of the nitric oxide (NO) system (endothelial, inducible, and neural NO synthases) and renin-angiotensin system (renin, angiotensinogen, and angiotensin II type 1A receptor) gene components in the kidneys of SBN/y (salt-resistant) and SBH/y (salt-sensitive) Sabra rat substrains, with and without deoxycorticosterone acetate (DOCA)-salt treatment. We also looked for immunocytochemical evidence of angiotensin II, the effector peptide of the renin-angiotensin system. Inducible and neural NO synthase gene expression values were lower in SBH/y than in SBN/y before and after DOCA-salt treatment. The gene expression level of endothelial NO synthase was not different in SBH/y and SBN/y, either with or without DOCA salt. Renin gene expression was significantly higher in kidneys of SBN/y than in kidneys of SBH/y rats, whereas angiotensinogen gene expression was significantly lower in SBN/y. After DOCA-salt treatment, renin gene expression was strongly suppressed in both strains but more so in SBH/y. Angiotensinogen gene expression, on the other hand, was increased by DOCA salt in SBN/y rats so that the two strains were no longer different. Angiotensin II immunoreactivity was significantly higher in SBN/y than in SBH/y; however, after DOCA salt, immunoreactivity in both strains was no longer detectable. Angiotensin II type 1A receptor gene expression was not different between the two strains, either before or after DOCA-salt administration. We conclude that DOCA salt induced a decrease in the activity of the renin-angiotensin system but did not change NO synthase gene expression in SBH/y and SBN/y. Inducible and neural NO synthase gene expression values were less in SBH/y than in SBN/y, independent of DOCA-salt administration. Thus, the NO system could explain, at least in part, the salt resistance of SBN/y.
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Expresión Génica , Óxido Nítrico Sintasa/genética , Ratas Mutantes/genética , Sistema Renina-Angiotensina/genética , Cloruro de Sodio/farmacología , Angiotensina II/metabolismo , Animales , Desoxicorticosterona/farmacología , Resistencia a Medicamentos/genética , Endotelio Vascular/enzimología , Inducción Enzimática , Hipertensión/inducido químicamente , Hipertensión/genética , Hipertensión/metabolismo , Inmunohistoquímica , Riñón/metabolismo , Masculino , Sistema Nervioso/enzimología , Ratas , Valores de ReferenciaRESUMEN
The vitamin D analogue, 22-oxacalcitriol [22-oxa-1,25(OH)2 vitamin D3], has pleiotropic effects similar to or greater than calcitriol but has markedly fewer calcemic and phosphatemic effects. To test the hypothesis that the lesser phosphatemic effect of 22-oxacalcitriol is due, at least in part, to a lack of interference with the phosphaturic effect of parathyroid hormone, acute clearance experiments were performed in parathyroidectomized rats receiving continuous 1-34 parathyroid hormone (PTH) infusion together with 22-oxacalcitriol (200 pmol.100 g body weight-1.min-1) or vehicle. In contrast to the previously reported inhibitory effect of calcitriol on PTH-induced phosphaturia, fractional excretion of phosphorus increased similarly in both groups, from 0.05 +/- 0.01 to 0.26 +/- 0.02 (p < 0.01) in the vehicle-infused animals and from 0.04 +/- 0.01 to 0.24 +/- 0.02 (p < 0.01) in the 22-oxacalcitriol-treated rats (p between groups not significant [n.s.]). Urinary cyclic AMP excretion also increased similarly, from 45.5 +/- 5.2 to 101.6 +/- 21.6 (p < 0.01) and from 45.4 +/- 5.6 to 102.6 +/- 16.7 pmol/min (p < 0.01), respectively (p between groups n.s.). In search for a nongenomic mechanism that might account for the disparate effects of 22-oxacalcitriol and calcitriol, OK cells, which are reminiscent of the mammalian proximal tubule cell, were stimulated with calcitriol and 22-oxacalcitriol and free intracellular calcium concentration was determined. At high concentrations, calcitriol caused a dose-dependent increase in [Ca2+]i; 22-oxacalcitriol had no effect on [Ca2+]i at any concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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Calcitriol/análogos & derivados , AMP Cíclico/metabolismo , Hormona Paratiroidea/antagonistas & inhibidores , Hormona Paratiroidea/farmacología , Fosfatos/orina , Animales , Calcitriol/farmacología , Calcio/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Masculino , Tasa de Depuración Metabólica , Ratas , Factores de TiempoRESUMEN
OBJECTIVE: This study was designed to test the hypothesis that non-genetic factors such as age, gonads and maternal environment modulate the expression of the salt-susceptibility genes and affect the blood pressure response to salt-loading (salt-sensitivity and salt-resistance) in the Sabra rat model of hypertension. METHODS: The blood pressure response to salt-loading was studied in Sabra hypertension prone (SBH/y) and Sabra hypertension resistant (SBN/y) rats of both sexes: (1) at 1, 3, 6, 9 and 12 months of age, (2) in adult rats after orchiectomy or oophorectomy, and (3) in animals that had been raised and nourished from birth to weaning by a foster mother from the contrasting strain. In each of the study protocols, systolic blood pressure was measured at baseline by the tail cuff method, animals were salt-loaded with deoxycorticosterone acetate, and blood pressure was measured again after 4 weeks. RESULTS: Basal blood pressure at all the ages studied and in both sexes was on average 10-15 mmHg higher in SBH/y than in SBN/y. Salt-loading in SBN/y of both sexes aged 1-12 months did not induce any significant increment in blood pressure. Salt-loading in SBH/y, in contrast, caused a highly significant rise in systolic blood pressure, of 40 mmHg or more at all the ages studied. There was no age difference or sex dependence in the magnitude of the blood pressure response to salt Oophorectomy or orchiectomy did not affect the levels of basal blood pressure nor prevent the hypertensive response to salt-loading in SBH/y or the lack of a hypertensive response in SBN/y rats. Gonadectomy did not affect blood pressure in salt-loaded hypertensive SBH/y nor in salt-loaded normotensive SBN/y. The basal blood pressure and the blood pressure responses of SBH/y and SBN/y of both sexes raised by foster mothers of the contrasting strains from birth to weaning were not different from those observed when raised by their natural mothers. CONCLUSIONS: This study indicates that salt-sensitivity in SBH/y and salt-resistance in SBN/y are not age-dependent phenomena; that the magnitude of the BP response to salt-loading is not sex-dependent; and that neither gonadectomy nor the maternal environment affect the blood pressure response to salt-loading in the adult animal of either strain. These non-genetic factors thus do not modulate expression of the salt-susceptibility genes in the Sabra genetic model of salt-sensitive hypertension.
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Modelos Animales de Enfermedad , Gónadas/fisiología , Hipertensión/etiología , Cloruro de Sodio Dietético/farmacología , Factores de Edad , Animales , Presión Sanguínea/efectos de los fármacos , Castración , Femenino , Masculino , Fenotipo , RatasRESUMEN
OBJECTIVES: Since the Sabra experimental model of hypertension was developed, it has been known as a model of salt-susceptible hypertension. Because the hypertensive response of the Sabra hypertension-prone strain (SBH/y) is classically elicited by salt loading with a combination of deoxycorticosterone acetate (DOCA) and salt, doubt has now been cast on whether the hypertensive response is due to sensitivity to salt or to mineralocorticoids. The present study was designed to resolve this question. MATERIALS AND METHODS: We studied the blood pressure response of SBH/y to various modes of salt loading. Animals were salt-loaded by administration of: 1% NaCl in drinking water and subcutaneous implantation of a 25 mg DOCA pellet (DOCA-salt); DOCA alone; 1% NaCl in drinking water alone; or 8% NaCl in chow alone. Blood pressure was determined by the tail-cuff method in awake and undisturbed animals. RESULTS: Within 4 weeks, the DOCA-salt treatment elicited the full hypertensive response previously reported in the SBH/y strain. Salt loading with 8% NaCl in chow reproduced the full hypertensive response observed with DOCA-salt, except that it occurred only after 7 weeks of treatment. Salt loading with DOCA alone raised blood pressure moderately and to a maximal level within 3 weeks; the magnitude of the blood pressure response was, however, significantly smaller than that observed with DOCA-salt or 8% NaCl in chow. Administration of 1% NaCl in water alone elicited no hypertensive response. CONCLUSIONS: The hypertensive response to salt loading in the Sabra experimental model of hypertension is an expression primarily of salt sensitivity, as it can be fully reproduced with salt alone, but not with DOCA alone. The use of the DOCA-salt mode of salt loading in this model, as opposed to salt loading with 8% salt in chow, is a useful way of accelerating the development of salt-sensitive hypertension in SBH/y, which shortens, and therefore facilitates, phenotyping.
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Presión Sanguínea/efectos de los fármacos , Desoxicorticosterona/efectos adversos , Modelos Animales de Enfermedad , Hipertensión/etiología , Cloruro de Sodio Dietético/efectos adversos , Animales , Presión Sanguínea/fisiología , Estudios de Seguimiento , Hipertensión/genética , Hipertensión/fisiopatología , Ratas , Ratas Endogámicas/genéticaRESUMEN
OBJECTIVE: To study the relationship between the sensitivity to sodium content of the diet in terms of development of hypertension and the regulation of the expression of type 1 angiotensin II receptor subtypes by such a diet. METHODS: The expression of angiotensin II receptor subtype (AT1A and AT1B) mRNAs was studied by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the four zones of the kidneys of Sabra rats, sensitive or resistant to DOCA salt-induced hypertension (SBH/y and SBN/y, respectively). Rats were fed a high (8%) or normal (0.4%) NaCl diet. As vasopressin is known to be elevated in SBH/y rats and to be involved in DOCA-salt hypertension, we studied an additional group of SBH/y rats, fed a high sodium diet, enriched in water. RESULTS: With the absence of DOCA, SBH/y rats did not develop hypertension. The high sodium diet induced a greater fall in the plasma renin activity in the SBH/y (-95%) than in the SBN/y (-63%). In the cortex (C) and inner stripe (IS), the high sodium diet decreased AT1A and AT1B mRNAs in SBH/y and SBN/y, with a higher magnitude for SBH/y, than for SBN/y (C, -28 versus -20%; IS, -42 versus -20%). The addition of water to the high sodium diet lessened the effect of sodium in the C and IS, although the plasma renin activity (PRA) was not altered. CONCLUSION: A high sodium diet significantly decreases both AT1A and AT1B gene expression in two specific zones of the rat kidney containing the target cells of angiotensin II (C and IS). This down-regulation is organ-specific since it was observed in the kidney and adrenals, but not in the liver. Finally, SBH/y and SBN/y rats differ in the basal level of AT1 mRNA expression in the IS, and in the ability to modulate AT1 mRNA level under sodium intake.
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Riñón/metabolismo , ARN Mensajero/biosíntesis , Receptores de Angiotensina/biosíntesis , Sodio/farmacología , Aldosterona/sangre , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Dieta , Hematócrito , Riñón/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Circulación Renal/efectos de los fármacos , Renina/sangre , Sodio/sangre , Urodinámica/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate whether mutations in the C-terminus of the three subunits of the rat epithelial sodium channel (alphabetagamma-rENaC) contribute to the hypertensive phenotype in five rat models for essential hypertension. DESIGN: We sequenced the C-terminal regions of alpha-, beta- and gamma-rENaC genes in five different hypertensive rat strains [spontaneously hypertensive rats (SHR), Dahl salt-sensitive (SS/Jr) rats, Milan hypertensive (MHS) rats, Sabra hypertensive (SBH) rats and Lyon hypertensive rats (LHR)] and their normotensive controls [Wistar-Kyoto (WKY) rats, Dahl salt-resistant (SR/Jr) rats, Milan normotensive (MNS) rats, Sabra normotensive (SBN) rats and Lyon normotensive rats (LNR)]. Identified polymorphisms were tested for cosegregation with blood pressure as well as for increased epithelial sodium channel (ENaC) activity. METHODS: Genomic DNA extracted from hypertensive and normotensive rat strains was amplified by the polymerase chain reaction and polymerase chain reaction fragments were sequenced. Cosegregation analysis was performed to test for correlations between blood pressure and different genotypes. The effects of a polymorphism on ENaC activity were assessed by functional expression in Xenopus laevis oocytes. The chromosomal location of the gene for gamma-ENaC was determined by linkage analysis in an F2 (MHS x MNS) population. RESULTS: We found no polymorphisms at the C-terminus of alpha- and beta-rENaC in the five rat models tested. We identified two polymorphisms at the C-terminus of the gamma-subunit, one leading to an amino acid change. Milan strains (MNS and MHS) were polymorphic for this mutation. By cosegregation analysis we could exclude the possibility that there was a correlation between blood pressure and this polymorphism. Functional expression of the polymorphism caused no increase in ENaC activity assessed by measurement of the amiloride-sensitive sodium current in Xenopus oocytes. The gene for the gamma-ENAC was located on rat chromosome 1. CONCLUSIONS: No polymorphisms at the C-terminus of the three subunits of the epithelial sodium channel cosegregating with blood pressure were detected in five different genetic rat models for hypertension. If an altered ENaC activity contributes to the pathogenesis of hypertension in these rats, it must thus arise from mutations in other parts of the protein, from mutations outside the coding region impairing the proper regulation of one of the subunits or from mutations in an ENaC-associated protein.
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Hipertensión/genética , Polimorfismo Genético , Canales de Sodio/genética , Animales , Epitelio/metabolismo , Hipertensión/metabolismo , Mutación , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
OBJECTIVES: Variations in the blood pressure response to salt-loading, the lack of quality control measures, and the need to prepare the strains for genetic studies led to renewed secondary inbreeding of the original colony of Sabra hypertension prone (SBH) and resistant (SBN) rats in order to regain genotypic and phenotypic homogeneity of the substrains. METHODS: Animals from the original breeding colony were selectively inbred for basal normotension and for susceptibility or resistance to the development of hypertension following salt-loading with deoxycorticosterone acetate (DOCA)-salt. Efficacy of inbreeding was tested by genome screening with 416 microsatellite primer sets. Phenotyping was based on measurements of systolic blood pressure by the tail-cuff methodology in awake, undisturbed animals maintained on standard diet and after salt-loading with DOCA-salt. Telemetric measurements of blood pressure were performed in a small number of animals to validate tail-cuff measurements. RESULTS: Animals from the new colony were designated SBH/y and SBN/y to differentiate from the original colony. Fourteen generations have been inbred over the past 4 years. Of the 402 microsatellites that amplified, 183 (45.5%) were polymorphic between the two substrains, and not a single locus was found to be heterozygous in either substrain. Phenotypic characteristics are provided for SBH/ y and SBN/y rats with respect to tail-cuff systolic blood pressure. The values obtained, which were validated by telemetry, demonstrate classical features of salt sensitivity or resistance, respectively. CONCLUSIONS: The genetic homogeneity found in SBH/y and SBN/y, the phenotype demonstrating salt-sensitivity or salt-resistance in terms of development of hypertension, and the relatively high frequency of informative genetic markers identify this Sabra rat model as highly suited for studies concerning the molecular genetics of gene-environment interactions affecting blood pressure regulation.
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Hipertensión/genética , Ratas Endogámicas/genética , Cloruro de Sodio/farmacología , Animales , Desoxicorticosterona/farmacología , Resistencia a Medicamentos , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Endogamia , Masculino , Repeticiones de Microsatélite , Fenotipo , Reacción en Cadena de la Polimerasa , RatasRESUMEN
Adenosine is a potent arterial vasodilator that, because of a short duration of action and acid lability, is ineffective in the oral treatment of hypertension. Y-341 is a synthetic adenosine analog that is acid stable and has a prolonged duration of action. It is highly selective for the A2 receptor, which is prevalent in the vascular smooth muscle and mediates vasodilation. To determine the efficacy of Y-341 as an antihypertensive agent, the effect of Y-341 on arterial pressure was studied in spontaneously hypertensive rats (SHR) in the awake state, 3 to 4 days after arterial cannulation. Y-341 (3 mg/kg) was dissolved in 5% DMSO and administered by gavage. Blood pressure and heart rate were monitored continuously at predetermined intervals. Fifteen minutes after administration, Y-341 reduced MAP from 180 +/- 4 to 126 +/- 2 mm Hg (n = 9, P < .001). There was no significant change in heart rate. The hypotensive effect was sustained over 8 h. Vehicle (n = 5) had no effect on blood pressure. The hypotensive effect was dose dependent when the dose of Y-341 was increased from 3 to 6 and 12 mg/kg. When Y-341 was administered at 3 mg/kg/day in a single dose for 5 consecutive days, there was no significant change in the magnitude of the hypotensive response over time.(ABSTRACT TRUNCATED AT 250 WORDS)
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Adenosina/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Receptores Purinérgicos P1/efectos de los fármacos , Adenosina/farmacología , Administración Oral , Animales , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores Purinérgicos P1/metabolismoRESUMEN
The effect of selective glucocorticoid or mineralocorticoid deficiency upon arterial pressure was evaluated in unanesthetized adult spontaneously hypertensive rats (SHR). Adrenalectomized SHR were replaced with 6 micrograms/24 h aldosterone (ALDO), 10 microgram/24 h dexamethasone (DEX), or both aldosterone and dexamethasone (ALDO + DEX) by IP osmotic mini-pumps. These were compared to sham-operated SHR (SHAM) and adrenalectomized SHR given no steroid replacement (ADX). Drinking fluid for all groups was 1% NaCl + 2.5% glucose. Six days after adrenalectomy, intra-arterial mean arterial pressure (MAP) fell from 174 +/- 2 to 149 +/- 6 mm Hg in ALDO (n = 8, P less than .01) and from 179 +/- 4 to 125 +/- 4 in ADX (n = 6, P less than .01). In contrast, MAP rose in SHAM from 171 +/- 4 to 179 +/- 5 mm Hg (n = 7, P less than .01), in ALDO + DEX from 161 +/- 3 to 184 +/- 4 mm Hg (n = 7, P less than .01), and in DEX from 162 +/- 2 to 181 +/- 4 mm Hg (n = 7, P less than .01). The results indicate that when diet salt intake is high, glucocorticoid action is necessary for the full expression of hypertension in adult SHR.
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Glucocorticoides/fisiología , Hipertensión/fisiopatología , Adrenalectomía , Aldosterona/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Dexametasona/administración & dosificación , Masculino , Mineralocorticoides/fisiología , Ratas , Ratas Endogámicas SHRRESUMEN
CS-905 is a dihydropyridine calcium channel antagonist which stands out for its prolonged hypotensive effect, and which is currently under investigation for the treatment of hypertension. The aim of the current series of studies was to investigate the effects of CS-905 on renal function in relation to its effects on arterial pressure. In anesthetized spontaneously hypertensive rats (SHR), intravenous bolus injection of CS-905 reduced mean arterial pressure (MAP) in a dose-dependent fashion. In parallel, there was a dose-related increase in urine flow (V), sodium excretion (UNaV), renal plasma flow (RPF), and glomerular filtration rate (GFR). In chronically cannulated unanesthetized SHR, single-dose CS-905 by gavage produced a sustained reduction in MAP, a significant increase in V and UNaV, no effect on RPF, and an increase in GFR. Continuous intrarenal infusion of CS-905 in anesthetized normotensive Munich Wistar rats at doses that did not affect MAP caused a marked diuresis and natriuresis, without affecting RPF or GFR. To determine whether the diuretic and natriuretic effects of CS-905 were mediated by changes in inner medullary blood flow, the effect of CS-905 on vasa recta blood flow (Qvr) was studied by fluorescent videomicroscopy in anesthetized normotensive Munich Wistar rats during continuous intrarenal infusion. At low infusion rates, CS-905 was diuretic and natriuretic while increasing Qvr. With a high infusion rate, although the diuretic and natriuretic effects of CS-905 were maximal, Qvr decreased. These findings suggest that the diuretic and natriuretic effects of CS-905 are dissociated from and cannot be accounted for by changes in RPF, GRF, or Qvr, and are most likely secondary to a direct action of CS-905 on renal tubule handling of sodium and water.
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Ácido Azetidinocarboxílico/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Diuresis/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Anestesia , Animales , Ácido Azetidinocarboxílico/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Infusiones Intravenosas , Inyecciones , Riñón , Médula Renal/irrigación sanguínea , Masculino , Ratas , Ratas Endogámicas SHR , Ratas EndogámicasRESUMEN
The effect of nifedipine monotherapy, retard tablets, 20 mg bid, was evaluated in 23 hypertensive patients, mean age, 79 +/- 2 years. Twenty-one patients completed an eight-week study. Blood pressure (BP) decreased to 160/90 mm Hg in 15 patients; in four additional patients diastolic BP dropped by 15% to 28%. In a subset of five patients with isolated systolic hypertension, a significant reduction in systolic BP was noted. Side effects were relatively mild and only two patients discontinued the study. The results suggest that nifedipine monotherapy offers an alternative, logic, therapeutic approach to hypertension in the elderly.