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1.
Therapie ; 72(6): 665-668, 2017 Dec.
Artigo em Francês | MEDLINE | ID: mdl-28939009

RESUMO

Due to the increasing use of fixed-dose combination therapy (FC) for treating several pathological conditions, the authors discuss their advantages (simplification of drug intakes and thus possible better compliance, rationale of pharmacological associations and drug dosages) and their disadvantages (limited dosage flexibility, possible misunderstanding of the co-administered drugs due to non-utilization of International nonproprietary name…) versus advantages and disadvantages of free drug combinations. Several recommendations are proposed. If FC is not in fact a problem in young adults with stable diseases, it should be cautiously prescribed for all the other patients, especially in elderly suffering from several diseases. FC should be only proposed after prescribing separately the different components, and should be regularly reassessed.


Assuntos
Combinação de Medicamentos , Adesão à Medicação , Preparações Farmacêuticas/administração & dosagem , Adulto , Fatores Etários , Idoso , Humanos , Erros de Medicação , Adulto Jovem
2.
Clin Exp Pharmacol Physiol ; 37(9): 894-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20456420

RESUMO

1. Visfatin (also known as nicotinamide phosphoribosyltransferase or Nampt) is a novel adipokine associated with metabolic abnormalities in obesity and diabetes. The aim of the present study was to determine whether visfatin levels in the circulation and visfatin expression in fat tissues are altered in Lyon hypertensive (LH) rats, a hypertensive strain with numerous metabolic abnormalities, and, if so, to explore the possible correlations between blood visfatin levels and the metabolic abnormalities in LH rats. 2. Male 18-20-week-old LH rats and their control, Lyon normotensive (LN) rats, were used. Blood pressure was recorded in conscious, unrestrained rats. Fat tissue weight was determined. Serum visfatin concentrations were determined by enzyme immunoassay, whereas visfatin expression in fat tissues was determined by western blotting. Relationships between two parameters were evaluated by linear regression analysis. 3. The LH rats had significantly higher bodyweight and fat tissue weight compared with LN rats. Serum lipid levels of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and triglyceride (TG) were all significantly higher in LH rats than in LN rats. Moreover, serum visfatin levels were higher in LH rats than in LN rats and were positively correlated with bodyweight, fat tissue weight and serum lipid levels (i.e. TC, HDL-C, LDL-C, TG and the TG:HDL-C ratio). There were no significant differences in serum glucose and insulin concentrations, or in the whole-body insulin resistance index, between LN and LH rats, and serum visfatin levels were not correlated with any of these parameters. Visfatin expression in visceral fat tissue, but not in subcutaneous fat tissue, was markedly upregulated in LH compared with LN rats. 4. In conclusion, the results of the present study demonstrate that serum visfatin levels in LH rats are elevated and are associated with lipid metabolic abnormalities.


Assuntos
Adipocinas/sangue , Hipertensão/metabolismo , Transtornos do Metabolismo dos Lipídeos/sangue , Nicotinamida Fosforribosiltransferase/sangue , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Índice de Massa Corporal , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Hipertensão/fisiopatologia , Insulina/sangue , Resistência à Insulina , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipídeos/sangue , Masculino , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/sangue , Obesidade/metabolismo , Ratos , Ratos Mutantes , Triglicerídeos/sangue
3.
J Cell Mol Med ; 13(4): 726-34, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19220584

RESUMO

Combinations therapy is often used in hypertensive patients whether combination therapy is necessary for preventing end-organ damage is not known. The objective of this study was to determine in four different hypertensive animal models the necessity of adding the calcium channel blocker amlodipine to therapy with the ss-blocker atenolol to modulate end-organ damage. Spontaneously hypertensive rats, DOCA-salt hypertensive rats, two-kidney, one-clip renovascular hypertensive rats and Lyon genetically hypertensive rats were used to study this objective. These animal models have different sensitivities to atenolol and amlodipine. The dosages of therapy employed were 10 mg/kg atenolol alone, 1 mg/kg amlodipine, 10 mg atenolol + 1 mg/kg amlodipine and 5 mg/kg atenolol+0.5 mg/kg amlodipine. BP was continuously recorded in all animals. After determination of baroreflex sensitivity, rats were sacrificed for end-organ damage evaluation. The combination of amlodipine and atenolol had a synergistic inhibitory effect on blood pressure and blood pressure variability, and end-organ damage as compared with monotherapy with atenolol or amlodipine in all animal models. Baroreflex sensitivity also improved with the combination therapy more than with monotherapy. In conclusion, atenolol and amlodipine combination exerts a superior effect on blood pressure, blood pressure variability, baroreflex sensitivity and end-organ damage. The superior effect of the combination was observed in all four models of hypertension.


Assuntos
Anlodipino/uso terapêutico , Atenolol/uso terapêutico , Hipertensão/tratamento farmacológico , Especificidade de Órgãos , Anlodipino/farmacologia , Animais , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Quimioterapia Combinada , Hemodinâmica/efeitos dos fármacos , Hipertensão/fisiopatologia , Masculino , Especificidade de Órgãos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Análise de Regressão , Fatores de Tempo
4.
Circ Res ; 100(7): 992-9, 2007 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-17332427

RESUMO

A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.


Assuntos
Pressão Sanguínea/genética , Mapeamento Cromossômico , Expressão Gênica , Hipertensão/genética , Peptídeos/genética , Locos de Características Quantitativas , Animais , Animais Congênicos , Aorta/metabolismo , Éxons , Hipertensão/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Íntrons , Rim/metabolismo , Miocárdio/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Peptídeos/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
5.
Bull Acad Natl Med ; 193(8): 1757-65; discussion 1766, 2009 Nov.
Artigo em Francês | MEDLINE | ID: mdl-20669540

RESUMO

Animal experimentation is of considerable importance in pharmacology and cannot yet be avoided when studying complex, highly integrated physiological functions. The use of animals has been drastically reduced in the classical phases of pharmacological research, for example when comparing several compounds belonging to the same pharmacological class. However, animal experiments remain crucial for generating and validating new therapeutic concepts. Three examples of such research, conducted in strict ethical conditions, will be used to illustrate the different ways in which animal experimentation has contributed to human therapeutics.


Assuntos
Experimentação Animal , Avaliação Pré-Clínica de Medicamentos , Animais , Humanos , Farmacologia
6.
Acta Pharmacol Sin ; 29(11): 1296-300, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18954523

RESUMO

AIM: The possibility that angiotensin-converting enzyme inhibitors can protect hypertensive kidneys independently of any blood pressure (BP) decrease remains a matter of controversy. The present study investigates this theory in Lyon genetically-hypertensive (LH) rats. METHODS: Male rats were used in the present study and were untreated (controls) or orally received 0.4, 0.1, 0.04, and 0.01 mg.kg(-1).d(-1) doses of perindopril from 3 to 17 weeks of age. At 16 and 23 weeks of age (ie during treatment and 6 weeks after its cessation), systolic BP (SBP) was measured by plethysmography, and urine was collected to measure the urinary protein (Uprot) and N-acetyl-seryl-aspartyl-lysyl-proline-to-creatinine (Cr) concentrations. The kidneys were dissected for a semiquantitative histological analysis. RESULTS: SBP was significantly lowered (-18%+/-2% and-11%+/-1% from controls at 16 and 23 weeks, respectively) with a 0.4 mg.kg(-1).d(-1) dose of perindopril. Lower doses did not affect SBP. Uprot/Cr decreased, and Ac-SDKP/Cr increased with all the doses of perindopril used. Uprot/Cr remained lower at 23 weeks in the rats treated with 0.1 mg.kg(-1).d(-1) and smaller doses. The ratio of Uprot/ Cr was closely (r=0.6) related to the histological lesions score. CONCLUSION: In LH rats, low doses of perindopril induce renoprotection which is independent of SBP decrease and persists after withdrawal of treatment.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Nefropatias/prevenção & controle , Perindopril/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Testes de Função Renal , Masculino , Proteinúria/prevenção & controle , Ratos
7.
Bull Acad Natl Med ; 191(4-5): 849-55; discussion 855-6, 2007.
Artigo em Francês | MEDLINE | ID: mdl-18225439

RESUMO

Genetically hypertensive rats of the Lyon strain (LH) have both high blood pressure and a metabolic syndrome. Linkage studies have disclosed quantitative trait loci of interest on chromosomes 2, 13 and 17. In the present work we designed consomic rats, i.e. LH rats in which a full chromosome was replaced by the same chromosome originating from the Brown-Norway (BN) normotensive strain. Rats consomic for chromosome 17 (LH-17BN) exhibited slightly but significantly lower blood pressure, which remained sensitive to an oral salt load. The cholesterol level was unaffected, while the triglyceride level was markedly depressed. This consomic approach seems to be of value for studying polygenic diseases such as hypertension and the metabolic syndrome. In the case of LH rats, our results confirm the functional importance of the loci identified on chromosome 17.


Assuntos
Hipertensão/genética , Doenças Metabólicas/genética , Fatores Etários , Animais , Pressão Sanguínea/fisiologia , Peso Corporal , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Masculino , Fenótipo , Ratos , Ratos Endogâmicos BN/genética , Ratos Endogâmicos/genética , Triglicerídeos/sangue
8.
Bull Acad Natl Med ; 190(1): 111-9; discussion 119-21, 2006 Jan.
Artigo em Francês | MEDLINE | ID: mdl-16878449

RESUMO

Human essential hypertension is due to interacting genetic and environmental factors. Spontaneously hypertensive rats have been genetically selected as models in this setting. The genetically hypertensive rat model that we have selected is the only one to associate mild hypertension with a "metabolic syndrome" (increased body weight, proteinuria and hyperlipidemia and elevated insulin/glucose ratio). This is a renin-dependent model of hypertension, in which low-dose (non antihypertensive) angiotensin-converting-enzyme inhibitor therapy affords significant and durable nephroprotection.


Assuntos
Modelos Animais de Doenças , Hipertensão/genética , Animais , Humanos , Hipertensão/fisiopatologia , Ratos
9.
J Hypertens ; 23(6): 1225-31, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15894899

RESUMO

OBJECTIVE: This study aimed to determine whether the alteration of the pressure natriuresis seen in Lyon genetically hypertensive (LH) rats occurs early, and the possible involvement in this alteration of the most important extra-renal factors that influence natriuresis. METHODS: In LH rats and their normotensive (LL) controls, acute pressure natriuresis was studied in denervated kidneys with or without controlling extra-renal influence; that is, adrenalectomy and an intravenous infusion of vasopressin, norepinephrine, hydrocortisone and aldosterone. RESULTS: With controlling the cited extra-renal influence, LH rats already exhibited, at 5 weeks of age, a slightly higher blood pressure (+9%) and a markedly reduced renal blood flow (-33%) compared with LL rats; their pressure-diuresis and pressure-natriuresis curves were significantly blunted. Between 16 and 50 weeks of age, although BP levels did not change, renal blood flow and glomerular filtration rate declined in LH rats while their pressure-diuresis and pressure-natriuresis curves continued to shift to higher pressures. When studied without controlling extra-renal influence, the values of pressure diuresis and natriuresis were significantly higher than in controlled conditions both in LH and LL rats. However, in 16-week-old rats, the LH/LL ratios for sodium and water excretion remained close under the two experimental conditions. CONCLUSIONS: The pressure-natriuresis function in LH rat shows early impairment and aggravates with age. This alteration is observed with, as well as without, controlling the influence of the main extra-renal factors that affect natriuresis.


Assuntos
Pressão Sanguínea , Hipertensão Renal/fisiopatologia , Natriurese , Doença Aguda , Fatores Etários , Animais , Taxa de Filtração Glomerular , Rim/fisiologia , Masculino , Ratos , Ratos Endogâmicos , Ratos Mutantes , Circulação Renal , Sódio/urina , Urina
10.
Physiol Genomics ; 8(1): 15-21, 2002 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-11842127

RESUMO

One or more quantitative trait locus (QTL) for blood pressure (BP) exists on rat chromosome 1, in the vicinity of the Sa gene. The present work examined whether this QTL region: 1) alters pressure-natriuresis relationship and 2) affects the BP response to salt load. Male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and rats from an SHR congenic strain that contains a WKY chromosome 1 segment spanning the BP QTL region (SHR. WKY-Sa) were used. In an acute study in anesthetized animals, renal function was measured at several levels of renal perfusion pressure. In a chronic study, BP was measured in freely moving rats using telemetry during normal and high sodium intake (2% NaCl as drinking water for 2 wk). WKY rats showed a significantly higher glomerular filtration rate and increased pressure-natriuresis compared with SHR. SHR.WKY-Sa also demonstrated an increased glomerular filtration rate and enhanced pressure-natriuresis, associated with a lower tubular sodium reabsorption, compared with SHR. These modifications were accompanied by a lower basal BP in SHR.WKY-Sa compared with SHR and a markedly reduced BP response to salt load. These findings suggest that the BP QTL(s) present in this region of chromosome 1 influences BP and salt sensitivity, at least partly, by modulating pressure-natriuresis.


Assuntos
Pressão Sanguínea/genética , Rim/fisiologia , Característica Quantitativa Herdável , Animais , Área Sob a Curva , Pressão Sanguínea/fisiologia , Mapeamento Cromossômico , Diástole/genética , Diástole/fisiologia , Rim/química , Testes de Função Renal , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Cloreto de Sódio na Dieta/metabolismo , Sístole/genética , Sístole/fisiologia
11.
J Hypertens ; 21(8): 1505-12, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12872044

RESUMO

OBJECTIVES: The nature of endothelial factors in response to acetylcholine (ACh) was investigated in conductance and resistance arteries from Lyon normotensive (LN) and Lyon hypertensive (LH) rats. Differences in endothelial function between the two strains were evaluated. METHODS AND DESIGN: Relaxations to ACh were studied in the aorta and small mesenteric arteries (SMA). The relative contribution of nitric oxide (NO), prostanoids and endothelial-derived hyperpolarizing factor (EDHF) was assessed using appropriate inhibitors. Western blot of endothelial NO synthase was achieved. The membrane potential of smooth muscle cells was assessed using microelectrodes. RESULTS: In LN rats, endothelium-dependent relaxation to ACh involved exclusively NO in the aorta, whereas both NO and EDHF were implicated in SMA. In the latter, relaxation was almost entirely prevented by blockade of either the NO or EDHF pathway, although ACh was still able to produce hyperpolarization in the presence of NO synthase and cyclooxygenase inhibitors. In LH rats, relaxation to ACh was unchanged in SMA but moderately depressed in the aorta, despite unchanged endothelial NO synthase protein expression and sensitivity to NO. In addition, indomethacin, but not a selective cyclooxygenase-2 inhibitor, significantly reduced ACh relaxations in the aorta from LH rats but not from LN rats. CONCLUSIONS: These results document differential endothelial function in a conductance and in resistance arteries from LN rats and LH rats. They show that simultaneous participation of NO and EDHF is required to promote relaxation in SMA from both strains, whereas NO alone accounts for relaxation in aorta from LN rats. In LH rats, aortic relaxation induced by ACh is slightly decreased despite the involvement of vasodilator products from cyclooxygenase-1.


Assuntos
Endotélio Vascular/fisiologia , Hipertensão/fisiopatologia , Resistência Vascular/fisiologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/fisiologia , Fatores Biológicos/metabolismo , Pressão Sanguínea , Peso Corporal , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores Enzimáticos/farmacologia , Hipertensão/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Prostaglandinas/metabolismo , Ratos , Ratos Endogâmicos , Ratos Mutantes , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
12.
J Hypertens ; 27(6): 1186-93, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19462495

RESUMO

BACKGROUND: Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RNO13) in several models of hypertension. METHODS: To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13BN) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13LH). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters. RESULTS: Compared with LH parents, LH-13BN rats showed decreased mean BP (up to -24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13LH and BN rats were much smaller than those observed between LH-13BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RNO13, despite the significant BP differences. CONCLUSION: The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Hipertensão/fisiopatologia , Ratos Endogâmicos SHR/genética , Ratos Endogâmicos SHR/fisiologia , Animais , Animais Congênicos , Doenças Cardiovasculares/etiologia , Mapeamento Cromossômico , Modelos Animais de Doenças , Humanos , Rim/fisiopatologia , Masculino , Locos de Características Quantitativas , Ratos , Ratos Endogâmicos BN , Renina/sangue , Fatores de Risco
13.
Fundam Clin Pharmacol ; 23(2): 169-78, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19298234

RESUMO

RhoA-activated kinase (ROK) is involved in the disorders of smooth muscle contraction found in hypertension model animals and patients. We examined whether the alpha1-adrenergic receptor agonist-induced ROK signal is perturbed in resistance small mesentery artery (SMA) of Lyon genetically hypertensive (LH) rats, using a ROK antagonist, Y27632. Smooth muscle strips of SMA and aorta were isolated from LH and Lyon normotensive (LN) rats. After Ca(2+)-depletion and pre-treatment with phenylephrine (PE), smooth muscle contraction was induced by serial additions of CaCl(2). In LH SMA Ca(2+) permeated cells to a lesser extent as compared with LN SMA, while CaCl(2)-induced contraction of LH SMA was greater than that of LN SMA, indicating a higher ratio of force to Ca(2+) in LH SMA contraction (Ca(2+) sensitization). No hyper-contraction was observed in LH aorta tissues. Treatment of LH SMA with Y27632 restored both Ca(2+) permeability and Ca(2+)-force relationship to levels seen for LN SMA. In response to PE stimulation, phosphorylation of CPI-17, a phosphorylation-dependent myosin phosphatase inhibitor protein, and MYPT1 at Thr853, the inhibitory phosphorylation site of the myosin phosphatase regulatory subunit, was increased in LN SMA, but remained unchanged in LH SMA. These results suggest that the disorder in ROK-dependent Ca(2+) permeability and Ca(2+)-force relationship is responsible for LH SMA hyper-contraction. Unlike other hypertensive models, the ROK-induced hyper-contractility of LH SMA is independent of MYPT1 and CPI-17 phosphorylation, which suggests that ROK-mediated inhibition of myosin phosphatase does not affect SMA hyper-contractility in LH SMA cells.


Assuntos
Amidas/farmacologia , Hipertensão/fisiopatologia , Piridinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Cálcio/metabolismo , Cloreto de Cálcio/farmacologia , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Contração Muscular/efeitos dos fármacos , Proteínas Musculares/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Fosfatase 1/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores
14.
Clin Exp Pharmacol Physiol ; 30(5-6): 413-8, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12859435

RESUMO

1. Because we previously observed that angiotensin AT2 receptor stimulation decreased pressure-natriuresis, in the present study we examined the possible involvement of these receptors in altered sodium excretion shown by Lyon hypertensive (LH) rats. 2. In 9-week-old male anaesthetized LH rats and normotensive (LL) controls pretreated with an angiotensin-converting enzyme inhibitor (quinapril; 10 mg/kg) and an AT1 receptor antagonist (losartan; 10 mg/kg), angiotensin (Ang) II was infused (30 ng/kg per min) to stimulate AT2 receptors. In other groups of rats, an AT2 receptor antagonist (PD123319; 50 micro g/kg per min) was added before AngII infusion. 3. During AT2 receptor stimulation, LH differed from LL rats by significantly reduced renal blood flow (RBF), glomerular filtration rate and pressure diuresis and natriuresis. The addition of PD123319 did not change total RBF, whereas it did increase pressure diuresis and natriuresis in both strains. However, the effects of PD123319 were less marked in LH rats than in LL rats. 4. These findings confirm that, under the present experimental conditions, AT2 receptors are antinatriuretic and are not of greater functional importance in hypertensive animals of the Lyon strain.


Assuntos
Hipertensão/genética , Rim/irrigação sanguínea , Rim/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Rim/efeitos dos fármacos , Masculino , Ratos , Receptor Tipo 2 de Angiotensina/agonistas , Receptor Tipo 2 de Angiotensina/genética , Especificidade da Espécie
15.
Am J Physiol Regul Integr Comp Physiol ; 283(5): R1041-5, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12376396

RESUMO

The present work aimed to assess, in Lyon hypertensive (LH) rats, whether an early and prolonged inhibition of the renin-angiotensin system (RAS) could result in a blood pressure (BP) lowering and nephroprotection that persist after its withdrawal. Male LH rats received orally from 3 to 12 wk of age either an angiotensin-converting enzyme inhibitor perindopril at the doses of 0.4 and 3 mg x kg(-1) x day(-1) or an AT(1) receptor antagonist losartan at the dose of 10 mg x kg(-1) x day(-1). BP, histological changes in the kidney, and urinary protein excretion were examined during and 10 wk after cessation of the treatments. Both perindopril and losartan decreased BP, prevented renal lesions, and limited urinary protein excretion. After cessation of the treatment, BP returned to the level of never-treated LH rats in rats having received 3 mg x kg(-1) x day(-1) of perindopril while it remained slightly lower in those treated with 0.4 mg x kg(-1) x day(-1) of perindopril or with losartan. This lack of marked persistent antihypertensive effect contrasted with a durable decrease in urinary protein excretion and improvement of the renal histological lesions. In conclusion, it is possible to separate the BP-lowering effects of RAS blockade from those on glomerulosclerosis and urinary protein excretion.


Assuntos
Pressão Sanguínea/fisiologia , Hipertensão Renal/fisiopatologia , Nefropatias/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Diurese/fisiologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Hipertensão Renal/genética , Hipertensão Renal/patologia , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Losartan/farmacologia , Masculino , Natriurese/fisiologia , Perindopril/farmacologia , Proteinúria/metabolismo , Ratos , Receptor Tipo 1 de Angiotensina
16.
Acta Pharmacol Sin ; 24(1): 1-6, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12511223

RESUMO

This paper reviews the data which demonstrate that Lyon genetically hypertensive (LH) rats exhibit a low renin form of hypertension. Since when compared to normotensive controls, LH rats exhibit a low renin release and are salt-sensitive. Despite this, the blockade of the renin-angiotensin system normalizes the blood pressure level and the regional blood flows in LH rats. Such a discrepancy between the compulsory presence of angiotensin II for the hypertension to develop and the low level of renin release seen in LH rats led to two hypotheses: 1) the existence of an early, short lasting increase of renin release which would be sufficient for the occurrence of a stable hypertension; 2) an hypersensitivity to the effects of angiotensin II. The study of the long-term effects of early short lasting blockades of the renin-angiotensin system allowed to exclude the first hypothesis. Concerning a hypersensitivity to the effects of angiotensin II, it was found to exist in the preglomerular vessels of LH rats. This increased response of renal vessels to angiotensin II may well explain the low renin form of hypertension of our model and therefore represents an important field for further research.


Assuntos
Hipertensão/genética , Modelos Animais , Renina/metabolismo , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Renina/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos
17.
Hypertension ; 43(1): 87-93, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14656956

RESUMO

In Lyon hypertensive (LH) rats, a model of low-renin genetic hypertension, we investigated adrenal sensitivity to angiotensin II in terms of angiotensin II receptor (AT1 and AT2 receptors) regulation, morphological changes, and aldosterone and corticosterone secretion. Twelve-week-old LH rats, compared with normotensive LN and LL rats, were either untreated or treated for 4 weeks with AT1 receptor antagonist irbesartan (50 mg/kg/d), angiotensin-converting enzyme inhibitor perindopril (3 mg/kg/d), or perindopril (3 mg/kg/d) plus angiotensin II infusion (200 ng/kg/min). At 16 weeks, untreated LH rats had high systolic blood pressure (P<0.05), low aldosterone (P<0.05), and increased corticosterone (P<0.05) plasma levels. AT1-receptor binding density in the zona glomerulosa was similar in the three strains. In LH rats, angiotensin II infusion increased the relative adrenal weight from 10.5+/-0.3 to 16.7+/-0.7 mg/100g (P<0.05), whereas this change was very modest in normotensive rats. Zona glomerulosa enlarged and plasma aldosterone increased after angiotensin II infusion in the 3 strains, but more markedly in LH versus normotensive rats (2.4- versus 1.3- and 1.6-fold, respectively; 20- versus 10-fold in normotensive rats, P<0.05). Surprisingly, after angiotensin II infusion, despite the absence of angiotensin II receptors in the three strains, the zona fasciculata-reticularis enlarged 1.5-fold and plasma corticosterone increased 1.7-fold only in LH rats (P<0.05), suggesting an indirect control of this compartment by angiotensin II. The hypertrophy and hypersecretory activity of both zona glomerulosa and zona fasciculata-reticularis in LH rats in response to angiotensin II point to the adrenal cortex as a pivotal tissue in the pathophysiology of hypertension in LH rats.


Assuntos
Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Angiotensina II/farmacologia , Hipertensão/metabolismo , Hipertensão/patologia , Córtex Suprarrenal/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Aldosterona/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Corticosterona/sangue , Hipertensão/genética , Masculino , Tamanho do Órgão , Ratos , Ratos Mutantes , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo
18.
Am J Physiol Renal Physiol ; 282(1): F51-8, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11739112

RESUMO

These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg. kg(-1). h(-1) iv) administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 +/- 1.2 vs. 5.4 +/- 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 +/- 0.6 vs. 6.1 +/- 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation (r(2) = 0.24 +/- 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 +/- 0.7 ml/min) and a lower limit of RBF autoregulation (P(LL) = 93 +/- 6 mmHg, defined as AP at RBF 5% below the plateau). After furosemide treatment, autoregulation curves (r(2) = 0.49 +/- 0.07) in SAD rats were shifted downward (plateau = 8.6 +/- 0.8 ml/min) and rightward (P(LL) = 102 +/- 5 mmHg). In five of six intact rats, P(LL) became measurable (104 +/- 1 mmHg), albeit with limited accuracy (r(2) = 0.09 +/- 0.03). In conclusion, the conscious SAD rat offers the possibility of describing RBF autoregulation curves under dynamic, unforced conditions. The tubuloglomerular feedback and myogenic mechanisms cooperate in setting P(LL) and thus in stabilizing RBF during spontaneous depressor episodes.


Assuntos
Pressão Sanguínea/fisiologia , Homeostase/fisiologia , Pressorreceptores/fisiologia , Circulação Renal/fisiologia , Animais , Aorta , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Estado de Consciência , Denervação , Diuréticos/farmacologia , Furosemida/farmacologia , Homeostase/efeitos dos fármacos , Masculino , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos
19.
Kidney Int ; 63(4): 1276-84, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12631344

RESUMO

BACKGROUND: Endothelins (ET) have diuretic and natriuretic actions via ETB receptors that are found in most renal tubular segments, although the thin limbs have not been studied. Data also suggest that dysfunction of the renal ET system may be important in the pathogenesis of hypertension. The present study was aimed at determining the presence and nature of ET receptors in the thin limbs of Henle's loop and their ability to activate a Ca2+-dependent signaling pathway, as well as whether ET-induced Ca2+ signals are altered in hypertension. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) and Fura 2 fluoreselected strains of Lyon rats with low-normal (LL), normal (LN), and high (LH) blood pressure. RESULTS: In SD rats, ET induced Ca2+ signals in DTL of long-looped nephrons, but not in DTL of short loops, or in ascending thin limbs. Ca2+ increases were abolished by BQ123, an antagonist of the ETA receptor, but not by BQ788, an antagonist of the ETB subtype. Endothelin-3 and sarafotoxin 6c, two ETB receptor agonists, were both inactive. RT-PCR showed the presence of both ETA and ETB receptor mRNA. Ca2+ signals measured scence measurements of [Ca2+]i were made to characterize ET receptors in descending thin limbs (DTL) of Sprague-Dawley rats, spontaneously hypertensive (SH) rats, and control Wistar-Kyoto (WKY) rats, and the three in DTL of WKY LL and LN rats were similar to those in Sprague-Dawley rats, but were significantly diminished (LH) or abolished (SH) in hypertensive rats. CONCLUSION: A functional ETA receptor activating a Ca2+-dependent pathway is expressed in DTL. This ETA-induced calcium signaling is impaired in two strains of genetically hypertensive rats.


Assuntos
Sinalização do Cálcio/fisiologia , Hipertensão/genética , Hipertensão/metabolismo , Alça do Néfron/metabolismo , Receptor de Endotelina A/metabolismo , Animais , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina B , Endotelina-1/metabolismo , Células Epiteliais/fisiologia , Túbulos Renais Coletores/metabolismo , Masculino , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Receptor de Endotelina A/genética
20.
Hypertension ; 44(5): 695-701, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15452030

RESUMO

The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.


Assuntos
Hipertensão/genética , Doenças Metabólicas/genética , Locos de Características Quantitativas , Animais , Antropometria , Pressão Sanguínea/fisiologia , Mapeamento Cromossômico , Cromossomos de Mamíferos , Ligação Genética , Metabolismo dos Lipídeos , Masculino , Modelos Animais , Fenótipo , Ratos/genética , Ratos Endogâmicos
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