RESUMO
Recent studies have reported potential roles of angiotensins in an adaptative physiological mechanism of protection against cerebral ischemia-induced neurological damages. In the present study, we examined the protective role of angiotensin IV (AngIV) in a rat model of embolic stroke induced by intracarotid injection of calibrated microspheres (50 microm). Internal carotid infusions of increasing doses of AngIV (0.01, 0.1 and 1 nmol/0.1 mL saline) dose dependently decreased mortality, neurological deficit and cerebral infarct size at 24 hours. With the highest dose of AngIV, mortality was reduced from 55 % in saline infused controls to 10 % (p=0.003), neurological deficit was reduced from 3.8 +/- 0.3 to 1.4 +/- 0.3 , (p<0.0001) and cerebral infarct size at 24 hours was decreased from 432 +/- 26 mm(3) to 185 +/- 19, (p=0.0001). The AT(4) antagonist divalinal-AngIV (10(-9) mol/0.1 mL), or pretreatment with L-NAME (10(-7) mol/0.1 mL), both completely abolished the protective effect of AngIV (1 nmol). The AT(2) antagonist PD123319 (10(-7) mol/0.1 mL) partially prevented the protective effect of AngIV on the neurological score. Sequential cerebral arteriographies revealed that AngIV induced a redistribution of blood flow to the ischemic areas within minutes. These results suggest that pharmacological doses of AngIV are protective against acute cerebral ischemia by triggering an AT(4)-mediated, NO-dependent intracerebral hemodynamic mechanism.
Assuntos
Angiotensina II/análogos & derivados , Isquemia Encefálica/tratamento farmacológico , Embolia Intracraniana/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Análise de Variância , Angiotensina II/administração & dosagem , Angiotensina II/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Encéfalo/irrigação sanguínea , Isquemia Encefálica/mortalidade , Isquemia Encefálica/fisiopatologia , Angiografia Cerebral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embolia Intracraniana/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Fluxo Sanguíneo Regional , Acidente Vascular Cerebral/tratamento farmacológico , Vasoconstrição/efeitos dos fármacosAssuntos
Hiperpotassemia/genética , Hipertensão/genética , Pseudo-Hipoaldosteronismo/genética , Adulto , Saúde da Família , Feminino , Genes Dominantes , Heterogeneidade Genética , Humanos , Hiperpotassemia/diagnóstico , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Pseudo-Hipoaldosteronismo/diagnósticoAssuntos
Anti-Hipertensivos/uso terapêutico , Benzotiadiazinas , Bloqueadores dos Canais de Cálcio/uso terapêutico , Infarto Cerebral/prevenção & controle , Hipertensão/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Diuréticos , Quimioterapia Combinada , HumanosRESUMO
OBJECTIVES: To evaluate compliance with antihypertensive therapy by a self-report in patients referred to hypertension specialists. METHODS: We studied 484 treated hypertensive subjects referred to several hypertension clinics and who were treated since at least one year. Patients were asked to fill in the Compliance Evaluation Test (CET), a questionnaire with 6 questions previously validated to assess factors that could affect medication compliance. We defined patients as "good compliant" when "No" was answered to the 6 items, as "minor noncompliant" when 1 or 2 "Yes" were answered, and as "noncompliant" when 3 or more "Yes" were answered. A good agreement was demonstrated between CET score and compliance evaluated by the number of pills missed during the previous month according to patient interview. RESULTS: We observed 8% of "noncompliant", 53% of "minor noncompliant" and 39% of "good compliant". [table: see text] Logistic regression analysis including age, sex, education level, blood pressure level and the number of antihypertensive tablets confirm the statistical differences observed. CONCLUSIONS: In clinical practice, a method of assessing medication compliance is to ask the patient for a self-report interview. We demonstrated that the compliance evaluation test is able to detect factors usually associated with poor compliance (young age, elevated blood pressure, number of tablets per day). The use of the compliance evaluation test may help physicians to face the problem of nonadherence among their hypertensive patients.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Cooperação do Paciente/estatística & dados numéricos , Idoso , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
Assuntos
Hipertensão/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Pseudo-Hipoaldosteronismo/genética , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Citoplasma/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Ligação Genética , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Junções Intercelulares/enzimologia , Peptídeos e Proteínas de Sinalização Intracelular , Íntrons , Túbulos Renais Coletores/enzimologia , Túbulos Renais Coletores/ultraestrutura , Túbulos Renais Distais/enzimologia , Túbulos Renais Distais/ultraestrutura , Masculino , Proteínas de Membrana/metabolismo , Microscopia de Fluorescência , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pseudo-Hipoaldosteronismo/enzimologia , Pseudo-Hipoaldosteronismo/fisiopatologia , Deleção de Sequência , Transdução de Sinais , Proteína Quinase 1 Deficiente de Lisina WNK , Proteína da Zônula de Oclusão-1RESUMO
1. Familial hyperkalaemic hypertension (FHH), also called pseudohypoaldosteronism type II (PHA2) or Gordon syndrome, is a rare Mendelian-form of low-renin hypertension. The first cases of FHH were reported approximately 30 years ago and they described the peculiar biochemical abnormalities (i.e. hyperkalaemia and hyperchloraemic acidosis despite a normal glomerular filtration rate). 2. Since then, more than 90 single cases and families have been reported in the literature. These various reports show marked differences in phenotype. 3. Our group has now collected 14 unrelated pedigrees originating from different parts of France and Europe. We confirm the large variations in the age of discovery and in the severity of the biochemical abnormalities from one individual to another and from one family to another one. 4. Blood pressure levels have no significant relationship with hyperkalaemia or hyperchloraemia, but there is a positive relationship with age, as in the normal population. 5. Analyses of clinical features and Mendelian segregation in our families demonstrate autosomal-dominant inheritance, as expected from the literature. 6. Efforts have been made in the past years to unravel the gene responsible for the disease. Until now, a primary responsibility of the gene encoding the thiazide-sensitive Na-Cl cotransporter (SLC12A3) has been excluded in PHA2 families. Three loci have been identified on chromosomes 1 (PHA2A), 17 (PHA2B) and 12 (PHA2C). 7. More recently, analysis of three additional pedigrees, including 10 affected subjects, with over 25 members allowed us to demonstrate further genetic heterogeneity and the existence of at least a fourth locus. 8. The genetic heterogeneity of this syndrome, and thus the variety of molecular defects, suggests the role of either several new components of the same pathway, multiple aldosterone- regulated effectors or direct or indirect partners of the Na-Cl cotransporter.
Assuntos
Heterogeneidade Genética , Hiperpotassemia/genética , Hiperpotassemia/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Adolescente , Adulto , Sequência de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , ATPase Trocadora de Sódio-Potássio/genética , SíndromeRESUMO
Previous studies have shown that angiotensin II (Ang II), by mediating rapid recruitment of collateral circulation, has a protective effect in the setting of acute ischaemia. In an experimental model of acute cerebral ischaemia in the gerbil, Fernandez et al. have reported that the mechanism of the protective effect of Ang 11 is blood pressure (BP)-independent, and that the AT1-receptor antagonist, losartan, but not the ACE inhibitor (ACE-I),enalapril, decreases mortality following unilateral carotid artery ligation. The aim of this study was to examine there producibility of the respective effects of losartan and enalapril, and to verify that these differential effects are drug class-related. Acute cerebral ischaemia was induced in anaesthetised gerbils bv unilateral carotid ligation. The effect of pretreatment with two different ACE-I(enalapril and lisinopril), and two different AT1-receptor antagonists (losartan and candesartan), administered orally or intravenously, on mortality were compared. Kaplan-Meier survival curves at day three were analysed bv a log-rank test. Pretreatment with both enalapril and lisinopril significantly decreased survival at day three compared with controls, while the AT1-receptor antagonists losartan and candesartan, despite similarly lowering BP, did not increase mortality. Coadministration of losartan and enalapril increased mortality to the same extent as enalapril alone. This study confirms that Ang II contributes to protective mechanisms against acute cerebral ischaemia through non AT1-receptor-mediated, BP-independent effects.
Assuntos
Anti-Hipertensivos/farmacologia , Isquemia Encefálica/tratamento farmacológico , Enalapril/farmacologia , Losartan/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Doença Aguda , Antagonistas de Receptores de Angiotensina , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Isquemia Encefálica/mortalidade , Modelos Animais de Doenças , Gerbillinae , Lisinopril/farmacologia , Masculino , Receptor Tipo 1 de Angiotensina , Receptores de Angiotensina/metabolismo , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/mortalidade , Tetrazóis/farmacologiaAssuntos
Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diltiazem/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Diuréticos/uso terapêutico , Quimioterapia Combinada , Humanos , Hipertensão/prevenção & controle , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: When positive end-expiratory pressure (PEEP) is applied, the intracavitary left ventricular end-diastolic pressure (LVEDP) exceeds the LV filling pressure because pericardial pressure exceeds 0 at end-expiration. Under those conditions, the LV filling pressure is itself better reflected by the transmural LVEDP (tLVEDP) (LVEDP minus pericardial pressure). By extension, end-expiratory pulmonary artery occlusion pressure (eePAOP), as an estimate of end-expiratory LVEDP, overestimates LV filling pressure when pericardial pressure is >0, because it occurs when PEEP is present. We hypothesized that LV filling pressure could be measured from eePAOP by also knowing the proportional transmission of alveolar pressure to pulmonary vessels calculated as index of transmission = (end-inspiratory PAOP--eePAOP)/(plateau pressure--total PEEP). We calculated transmural pulmonary artery occlusion pressure (tPAOP) with this equation: tPAOP = eePAOP--(index of transmission x total PEEP). We compared tPAOP with airway disconnection nadir PAOP measured during rapid airway disconnection in subjects undergoing PEEP with and without evidence of dynamic pulmonary hyperinflation. DESIGN: Prospective study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: We studied 107 patients mechanically ventilated with PEEP for acute respiratory failure. Patients without dynamic pulmonary hyperinflation (group A; n = 58) were analyzed separately from patients with dynamic pulmonary hyperinflation (group B; n = 49). INTERVENTION: Transient airway disconnection. MEASUREMENTS AND MAIN RESULTS: In group A, tPAOP (8.5+/-6.0 mm Hg) and nadir PAOP (8.6+/-6.0 mm Hg) did not differ from each other but were lower than eePAOP (12.4+/-5.6 mm Hg; p < .05). The agreement between tPAOP and nadir PAOP was good (bias, 0.15 mm Hg; limits of agreement, -1.5-1.8 mm Hg). In group B, tPAOP (9.7+/-5.4 mm Hg) was lower than both nadir PAOP and eePAOP (12.1+/-5.4 and 13.9+/-5.2 mm Hg, respectively; p < .05 for both comparisons). The agreement between tPAOP and nadir PAOP was poor (bias, 2.3 mm Hg; limits of agreement, -0.2-4.8 mm Hg). CONCLUSIONS: Indexing the transmission of proportional alveolar pressure to PAOP in the estimation of LV filling pressure is equivalent to the nadir method in patients without dynamic pulmonary hyperinflation and may be more reliable than the nadir PAOP method in patients with dynamic pulmonary hyperinflation.
Assuntos
Pressão Sanguínea/fisiologia , Cuidados Críticos , Pulmão/fisiopatologia , Respiração com Pressão Positiva , Insuficiência Respiratória/terapia , Função Ventricular Esquerda/fisiologia , Idoso , Diástole/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Alvéolos Pulmonares/fisiopatologia , Edema Pulmonar/fisiopatologia , Edema Pulmonar/terapia , Pressão Propulsora Pulmonar/fisiologia , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/fisiopatologiaRESUMO
BACKGROUND: It is well established that prednisone above 7.5 mg/day may induce osteopenia in association with decreased bone formation. In contrast, the effect of cyclosporine on bone remodeling and bone mineral density (BMD) is controversial. Multiple confounding factors explain this controversy, especially after renal transplantation. METHODS: Fifty-two renal transplanted patients never exposed to aluminum while on dialysis were selected because they had no rejection and no hypercalcemia for 24 months while being treated with low dose prednisone/cyclosporine A (daily dose at 10 mg and 4.8 mg/kg, respectively, beyond 3 months). Bone remodeling markers (BRMs; plasma osteocalcin, bone and total alkaline phosphatases for formation, and urinary pyridinolines for resorption) were sequentially measured together with plasma creatinine, intact parathyroid hormone (PTH) and 25 OH vitamin D and cyclosporine from day 0 to 24 months. BMD was measured at 3, 6, 12, and 24 months by quantitative computerized tomography (QCT) at the lumbar spine and by double-energy x-ray absorptiometry (DEXA) at this site, as well as at the femoral neck, radius shaft, and ultradistal (UD) radius. RESULTS: Plasma concentrations of creatinine, PTH, and 25 OH vitamin D initially decreased and stabilized beyond three months at 137 micromol/L, 1.5 the upper limit of normal (ULN) and 11 ng/mL, respectively. All BRM increased significantly above the ULN at six months and then decreased. The BMD Z score at three months was low at all sites measured by DEXA and QCT. Follow-up measurements showed stability of absolute value and of Z score at all sites measured by DEXA. A comparison of the lumbar QCT Z score, which was available in 42 patients at 3 and 24 months, showed an increase in 28 and a decrease in 14, so that the increase for the whole group was significant (P < 0.04). Compared with patients with a decreased Z score, those with an increased Z score had significantly higher cyclosporine and lower prednisone dosages and a greater BRM increase at six months, whereas age, sex ratio, and plasma creatinine, PTH and 25 OH vitamin D were comparable and stable from months 3 through 24. The mean trough level of cyclosporine for the first six months was positively correlated to osteocalcin and total alkaline phosphatase increase at six months, and both bone formation and resorption marker increases were significantly correlated to the lumbar QCT Z score increase at 24 months. CONCLUSIONS: Combined low-dose prednisone and cyclosporine immunosuppression are associated with a stabilization of BMD measured at all sites with DEXA 3 to 24 months after renal transplantation and with a prevention of age-related loss of vertebral trabecular bone, as shown by the significant increase in lumbar spine QCT Z score. It is suggested that cyclosporine, together with the decrease of prednisone dosage but independent of renal function, PTH, and vitamin D status, contributes to a transient stimulation of bone remodeling at six months, which counterbalances the deleterious effect of prednisone on bone formation and BMD.
Assuntos
Anti-Inflamatórios/efeitos adversos , Doenças Ósseas Metabólicas/prevenção & controle , Remodelação Óssea/efeitos dos fármacos , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Prednisona/efeitos adversos , Absorciometria de Fóton , Adulto , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Doenças Ósseas Metabólicas/tratamento farmacológico , Feminino , Colo do Fêmur , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Humanos , Falência Renal Crônica/cirurgia , Vértebras Lombares , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Rádio (Anatomia) , Resultado do TratamentoRESUMO
Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.
Assuntos
Cromossomos Humanos Par 12/genética , Genes Dominantes/genética , Heterogeneidade Genética , Hipertensão/genética , Pseudo-Hipoaldosteronismo/genética , Simportadores , Acidose/genética , Acidose/fisiopatologia , Adulto , Alelos , Proteínas de Transporte/genética , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , França , Haplótipos/genética , Humanos , Hiperpotassemia/genética , Hiperpotassemia/fisiopatologia , Hipertensão/fisiopatologia , Escore Lod , Masculino , Mutação/genética , Linhagem , Pseudo-Hipoaldosteronismo/fisiopatologia , Simportadores de Cloreto de SódioRESUMO
HISTOLOGICAL AND FUNCTIONAL CONSEQUENCES OF ESWL: Extracorporeal shock wave litotripsy is now used for the treatment of about 90% of stones. Because of the nonpunctual delivery of energy into the stone, a small volume of renal parenchyma is injured, giving rise to a fibrous scar which can be visualized by morphological techniques such as magnetic nuclear resonance. Isotopic techniques point out a 15% reduction of renal plasma flow on the side of the litotripsy. For a majority of patients, this alteration is transient. HYPERTENSION: In a few cases, abrupt onset of transient hypertension has been reported in clear relation with a compressive perirenal hematoma. The causal effect of ESWL on late occurrence of permanent hypertension is however still uncertain, probably because of the difficulty to show that this occurrence is not related to the older age of the patient alone. The FDA sponsored multicentric study begun in 1993 should solve this issue in the future. PATIENTS AT RISK: Recent articles suggest that altered renal function prior to ESWL would predict late occurrence of hypertension and worsening of renal failure. Furthermore, age and the resistance index of arcuate or interlobular renal arteries (measured by Doppler) could help to screen the patients at risk of developing hypertension. Practical attitude: In practice, renal function and blood pressure should be carefully monitored in patients aged over 60 and/or who have a serum creatinine > 300 mumol/l.