RESUMO
Neutral endopeptidase (NEP) hydrolyses angiotensins (Ang) I and II and generates angiotensin-(1-7) [Ang-(1-7)]. In humans, the insertion/deletion (I/D) angiotensin-I converting enzyme (ACE) gene polymorphism determined plasma ACE levels by 40%. In rats, a similar polymorphism determines ACE levels which are inversely associated to NEP activity. The objective of this study is to evaluate the relationship between ACE expression and plasma NEP activity in normotensive subjects and in hypertensive patients. In total, 58 consecutive patients with hypertension, evaluated in our Hypertension Clinic, were compared according to their ACE I/D genotypes with 54 control subjects in terms of both plasma ACE activity and NEP activities. Plasma ACE activity was elevated 51 and 70% in both DD ACE groups (normotensives and hypertensives) compared with their respective ID and II ACE groups (P<0.001). A significant effect of the ACE polymorphism and of the hypertensive status on ACE activity was observed (P<0.001). In normotensive DD ACE subjects, NEP activity was 0.30+/-0.02 U/ml, whereas in the normotensive II ACE and in the normotensive ID ACE subjects NEP activity was increased 65 and 48%, respectively (P<0.001). In the hypertensive DD ACE patients, NEP activity was 0.47+/-0.03 U/mg. An effect of the I/D ACE genotypes on NEP activity (P<0.04) and an interaction effect between the I/D ACE genotype and the hypertensive status were also observed (P<0.001). These results are consistent with a normal and inverse relationship between the ACE polymorphism and NEP activity in normotensive humans (as is also observed in rats). This normal relationship is not observed in hypertensive patients.
Assuntos
Hipertensão/enzimologia , Neprilisina/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Análise de Variância , Estudos de Casos e Controles , DNA/sangue , Ecocardiografia , Feminino , Genótipo , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Neprilisina/sangue , Peptidil Dipeptidase A/sangueRESUMO
INTRODUCTION: Angiotensin II levels can be partially inhibited during chronic administration of angiotensin converting enzyme (ACE) inhibitors, limiting from a clinical point of view its efficacy in the treatment of hypertension. There are few studies relating ACE activity directly with early prevention of left ventricular hypertrophy (LVH) in systemic hypertension during the administration of an ACE inhibitor (ACEI). AIM: To evaluate the effects of early ACE inhibition with perindopril on the development of hypertension, LVH and levels of angiotensin II (Ang II) in plasma as well as in LV in the rat Goldblatt model (Gb; 2 kidneys-1 clip), 2 weeks after surgery. RESULTS: Systolic blood pressure and relative LV mass increased by 42% and 20% respectively, in the Gb group (p < 0.001). Plasma and LV ACE activities were significantly higher in the Gb rats compared with the control rats. Plasma and LV Ang II levels also increased by 129% and 800%, respectively. Perindorpil prevented hypertension and LVH development by inhibiting plasma ACE (and also LV ACE), and also circulation Ang II in plasma and in the LV. CONCLUSIONS: In this experimental model of hypertensive LVH, there is an early activation of plasma and cardiac ACE. Early administration of an ACE inhibitor prevents the development of hypertension and LVH by inhibiting the increases of plasma and LV Ang II.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/prevenção & controle , Perindopril/administração & dosagem , Angiotensina II/análise , Angiotensina II/sangue , Animais , Anti-Hipertensivos/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Hipertensão/enzimologia , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Peptidil Dipeptidase A/análise , Peptidil Dipeptidase A/sangue , Ratos , Ratos Sprague-DawleyRESUMO
Angiotensin I is a substrate for both ACE and for neutral endopeptidase 24.11 (NEP). We hypothesized that high ACE expression is related to low NEP activity. Accordingly, circulating and tissue NEP and ACE activities were measured by fluorometry in homozygous rats (F(0) and F(2)) for the Lewis microsatellite allele (LL, low ACE) and for the Brown Norway microsatellite allele (BB, high ACE). Plasma, lung, and aortic ACE activities in F(0) and F(2) were higher in BB rats than in LL rats (P<0.01), whereas left ventricular ACE activity was similar in both genotypes. In contrast, NEP activity in the LL group was higher in the serum, aorta, and lungs in F(0) and F(2) homozygous (P<0.05). Plasma ACE activity was inversely correlated with serum (r=-0.6 and -0.598 in F(0) and F(2), respectively; P<0.03) and lung NEP activities (r=-0.77 in F(0) and r=-0.59 in F(2), P<0.01). Aortic ACE and NEP activities were also correlated (r=-0.696 and -0.584 in F(0) and F(2), respectively; P<0.03). In conclusion, genetically determined high ACE expression in rats is inversely related to tissue NEP activity, which could determine lower angiotensin-(1-7) tissue levels.
Assuntos
Endopeptidases/metabolismo , Peptidil Dipeptidase A/metabolismo , Animais , Aorta/enzimologia , Pressão Sanguínea/fisiologia , Endopeptidases/sangue , Feminino , Genótipo , Ventrículos do Coração/enzimologia , Pulmão/enzimologia , Masculino , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos LewRESUMO
The aim of this study was to estimate the prevalence of the different alleles of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and associated plasma ACE activity, as well as cardiac echocardiographic structure, in a healthy Chilean population. We selected 117 healthy normotensive subjects (aged 45 to 60 years, middle socioeconomic status, nonobese, and nondiabetic) from a population-based study concerning the prevalence of risk factors for chronic diseases (Conjunto de Acciones Para la Reducción Multifactorial de las Enfermedades no Transmisibles [CARMEN]). The frequencies of the I and D alleles were 0.57 and 0.43, respectively. Mean plasma ACE activity was 15.3 +/- 3.9 U/mL. Compared with subjects with the II genotype, plasma ACE activity was significantly higher in subjects with the ID and DD genotypes with no difference between them. No correlation was observed between blood pressure and plasma ACE activity. Among the three different genotypes there was no difference in left ventricular (LV) dimensions or in LV mass. No correlation between plasma ACE activity and LV mass was observed for either gender or different genotypes. Multivariate linear regression analysis using LV mass and LV mass index as dependent variables showed independent effects (P < .05) for gender (higher LV mass in men) and diastolic blood pressure, but not for the DD genotype. In conclusion, in this population, the presence of the D allele on the ACE gene determined higher circulating ACE activity. However, in this normotensive healthy population, male gender and diastolic blood pressure, but not the presence of the D allele, were associated with increased LV mass.
Assuntos
Elementos de DNA Transponíveis/genética , Deleção de Genes , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Função Ventricular , Alelos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Chile , Doença Crônica , DNA/análise , Primers do DNA/química , Ecocardiografia , Feminino , Marcadores Genéticos/genética , Genótipo , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Reação em Cadeia da Polimerase , Valores de Referência , Fatores de Risco , Espectrometria de Fluorescência , Inquéritos e QuestionáriosRESUMO
There is evidence that insulin-like growth factor-1 (IGF-1) plays a role in the development of left ventricular hypertrophy, but it is uncertain whether cardiac IGF-1 changes before or after hypertension is established, and whether circulating IGF-1 are involved in cardiac hypertrophy. We have investigated changes in circulating and left ventricular IGF-1 and in the expression of the IGF-1 gene in the left ventricles of rats during the development of hypertensive left ventricular hypertrophy (Goldblatt model; 2 kidney-1 clamped). Our results show that the left ventricular contents of IGF-1 and its mRNA were increased at one and four weeks of hypertension and hypertrophy, and that both returned to control values after nine weeks. These changes were unrelated to the seric concentration of IGF-1 in the blood. These results show that local rather than circulating IGF-1 levels contributed to the development of renovascular hypertensive left ventricular hypertrophy.
Assuntos
Hipertrofia Ventricular Esquerda/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Miocárdio/metabolismo , Animais , Modelos Animais de Doenças , Expressão Gênica , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hipertensão Renovascular/complicações , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Fator de Crescimento Insulin-Like I/genética , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
OBJECTIVE: To evaluate regression of experimental left ventricular hypertrophy (LVH) in terms of its effects both on myocardial collagen levels and on diastolic stiffness. METHODS: Two-kidney, one clip Goldblatt hypertensive rats were left untreated for 4 weeks (HT4W, n = 12) or 12 weeks (HT12W, n = 11) and compared with rats the treatment of which was started after 4 weeks of hypertension with 30 mg/kg per day losartan for 8 weeks (LOS, n = 12), or 50 mg/l enalapril for 8 weeks (ENA, n = 11). A group of sham-operated rats served as controls (SHAM, n = 9). RESULTS: The blood pressure of the rats increased significantly and LVH developed both after 4 and after 12 weeks of hypertension. Treatment with losartan or enalapril significantly decreased blood pressure and induced complete regression of LVH. Myocardial hydroxyproline concentrations increased in groups HT4W and HT12W (530 +/- 153 and 581 +/- 111 micrograms/g, respectively) relative to that in the SHAM group (421 +/- 22 micrograms/g). None of the treatments induced regression of increased myocardial collagen levels. The slopes of the end-diastolic stress-strain relationships in the isolated beating hearts were significantly higher in HT4W, HT12W and in both treated groups compared with those in the SHAM group, indicating increased diastolic myocardial stiffness. CONCLUSION: Losartan and enalapril treatments decreased blood pressure and induced complete regression of LVH in this model of renovascular hypertension. In contrast, none of the treatments induced regression of increased myocardial collagen levels or reduced the abnormal left ventricular diastolic stiffness. These data suggest that diastolic dysfunction depends more on increased myocardial collagen levels than it does on myocardial mass in this model of pathological LVH.
Assuntos
Colágeno/análise , Diástole , Hipertensão Renovascular/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Miocárdio/química , Animais , Compostos de Bifenilo/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Enalapril/uso terapêutico , Hipertensão Renovascular/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Imidazóis/uso terapêutico , Losartan , Masculino , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/fisiologia , Tetrazóis/uso terapêuticoRESUMO
The role of cyclic AMP-dependent protein kinase (PKA) and systolic function during the development of left ventricular hypertrophy (LVH) still remain uncertain. The aim of this work is to study PkA activity and mechanical heart function in two experimental heart hypertrophy models: specifically, one induced by pressure overload (Goldblatt model: two kidneys, one clamped, Gb); and another secondary to myocardial infarction (MI) generated by ligation of the left coronary artery. Hypertension in the Gb group becomes evident by the third and fourth week after surgery without any significant change in the corresponding sham group. The myocardial infarction group did not show any change in systolic pressure. Different degrees of LVH for the two experimental models were observed. Relative cardiac mass (RCM) and relative ventricular mass (RVM) increased 23 and 16%, respectively, above the sham-operated rats in MI group (P < 0.05). For the pressure overload model, the increase values were 42 and 44%, respectively (P < 0.05). Left ventricular hypertrophy was also evaluated through quantitative changes in cardiac beta-myosin heavy chain which agreed with morphometric studies in Goldblatt rats. Ventricular PKA activity did not show any significant difference with respect to the sham-operated group after induction of pressure overload. For the MI model, ventricular PKA activity changed only at day 7 post-infarction with a 289% increase above the sham-operated group (P < 0.05). The absence of activation of ventricular PKA after constriction of renal artery or myocardial infarction was also corroborated by the patterns of PKA-dependent phosphorylated proteins. While force-generating capacity was increased, there was no change in ventricular PKA activity, indicating that there is no relation between this enzyme and systolic stress-strain regression lines in either pressure overload or myocardial infarction conditions. Cyclic AMP-dependent protein kinase activity had no relation with development of cardiac hypertrophy in the two experimental models of LVH. These findings contribute to the hypothesis for a multifactorial interaction of different intracellular biochemical and molecular mechanisms in the genesis of cardiac hypertrophy.
Assuntos
Cardiomegalia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipertensão Renovascular/complicações , Infarto do Miocárdio/complicações , Animais , Cardiomegalia/enzimologia , Cardiomegalia/etiologia , Cardiomegalia/fisiopatologia , Ventrículos do Coração/enzimologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Structural and biochemical modifications of the myocardium (remodeling) occur after acute myocardial infarction. An important part of this process of myocardial remodeling takes place in the interstitial compartment which is composed mainly of fibrillar collagen. These remodeling changes are associated with modifications in left ventricular geometry and function that could be deleterious and have significant clinical manifestations. Some salutary effects of the treatment are related to modifications of the process of interstitial remodeling. Clinical studies with calcium channel antagonists, nitrates and, specially converting enzyme inhibitors have shown significant improvement in the degree of ventricular dilation, hemodynamics and exercise tolerance as a compared to placebo treated patients. Ongoing clinical studies will provide us with more definite information on the effects of converting enzyme inhibitors on long term prognosis as well as on myocardial remodeling after acute myocardial infarction.