RESUMO
The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.
Assuntos
Diástole , Estrogênios/metabolismo , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Fatores Etários , Animais , Diástole/efeitos dos fármacos , Modelos Animais de Doenças , Terapia de Reposição de Estrogênios , Estrogênios/deficiência , Estrogênios/uso terapêutico , Feminino , Humanos , Óxido Nítrico Sintase/metabolismo , Pós-Menopausa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina , Fatores de Risco , Fatores Sexuais , Transdução de Sinais , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of cardiac hypertrophy, remodeling, and heart failure. Estrogen attenuates the effects of an activated circulating RAS; however, its role in regulating the cardiac RAS is unclear. Bilateral oophorectomy (OVX; n = 17) or sham-operation (Sham; n = 13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, the rats were randomized and received either 17 ß-estradiol (E2, 36 µg/pellet, 60-day release, n = 8) or vehicle (OVX-V, n = 9) for 4 weeks. The rats were sacrificed, and blood and hearts were used to determine protein and/or gene expression of circulating and tissue RAS components. E2 treatment minimized the rise in circulating angiotensin (Ang) II and aldosterone produced by loss of ovarian estrogens. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7) content, chymase gene expression, and mast cell number. Neither OVX nor OVX+E2 altered cardiac expression or activity of renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R). E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7) mas receptor, in comparison to sham-operated and OVX littermates. E2 treatment appears to inhibit upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly by reducing chymase-dependent Ang II formation. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.
Assuntos
Estrogênios/farmacologia , Miocárdio/metabolismo , Ovariectomia , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/metabolismo , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Animais , Western Blotting , Quimases/genética , Quimases/metabolismo , Estradiol/sangue , Estradiol/metabolismo , Estradiol/farmacologia , Estrogênios/sangue , Estrogênios/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Mastócitos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Fragmentos de Peptídeos/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Ratos Transgênicos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Knowledge of hemodynamic factors accounting for the development of hypertension should help to tailor therapeutic approaches and improve blood pressure control. Few data exist regarding sex differences of hemodynamic factors contributing to hypertension progression among patients with untreated nondiabetic stage I and II prehypertension (PreHyp) as defined by the Joint National Committee-7 guidelines (JNC-7). METHODS: We utilized noninvasive impedance cardiography, applanation tonometry and plasma measures of angiotensin II, angiotensin (1-7), serum aldosterone, high-sensitivity C-reactive protein (hs-CRP) and cytokine biomarkers of inflammation to characterize the hemodynamic and hormonal profile of 100 patients with untreated hypertension (39 women). RESULTS: Despite there being no differences between women and men in terms of office blood pressure, heart rate and body mass index, men demonstrated lower values of pulse pressure, systemic vascular resistance, brachial artery pulse wave velocity and augmentation index. In each of the three hypertension categories, the increased blood pressure in men was associated with significant augmentations in stroke volume and cardiac output compared with women. Sex-related hemodynamic differences were associated in women with higher plasma levels of leptin, hs-CRP, plasma angiotensin II and serum aldosterone, and no differences in the serum concentrations of cytokinins. In women but not men, hs-CRP correlated with plasma concentrations of transforming growth factor ß1 (TGFß1) and body weight; in addition, plasma TGFß1 correlated with levels of serum vascular cell adhesion molecule 1. CONCLUSION: The impact of sex differences in the hemodynamic factors accounting for the elevation in arterial pressure in subjects with essential hypertension has been poorly characterized or this information is not available. We suggest that this gap in knowledge may adversely influence choices of drug treatment since our study shows for the first time significant differences in the hemodynamic and hormonal mechanisms accounting for the increased blood pressure in women compared to men.
Assuntos
Hemodinâmica , Hormônios/sangue , Hipertensão/sangue , Hipertensão/fisiopatologia , Biomarcadores/sangue , Cardiografia de Impedância , Feminino , Humanos , Hipertensão/diagnóstico , Mediadores da Inflamação/sangue , Masculino , Manometria , Pessoa de Meia-Idade , Pré-Hipertensão/sangue , Pré-Hipertensão/diagnóstico , Pré-Hipertensão/fisiopatologia , Prognóstico , Sistema Renina-Angiotensina , Fatores SexuaisRESUMO
OBJECTIVE: mRen2.Lewis rats exhibit exacerbated increases in blood pressure, left ventricular (LV) remodeling, and diastolic impairment after the loss of estrogens. In this same model, depletion of estrogens has marked effects on the cardiac biopterin profile concomitant with suppressed nitric oxide release. With respect to the establishment of overt systolic hypertension after oophorectomy (OVX), we assessed the effects of timing long-term 17ß-estradiol (E2) therapy on myocardial function, myocardial structure, and the cardiac nitric oxide system. METHODS: OVX (n = 24) or sham operation (Sham; n = 13) was performed in 4-week-old female mRen2.Lewis rats. After randomization, OVX rats received E2 immediately (OVX + E2-early; n = 7), E2 at 11 weeks of age (OVX + E2-late; n = 8), or no E2 at all (OVX; n = 9). RESULTS: E2-early was associated with lower body weight, less hypertension-related cardiac remodeling, and decreased LV filling pressure compared with OVX rats without E2 supplementation. E2-late similarly attenuated the adverse effects of ovarian hormone loss on tissue Doppler-derived LV filling pressures and perivascular fibrosis, and significantly improved myocardial relaxation or mitral annular velocity (e'). Early and late exposures to E2 decreased dihydrobiopterin, but only E2-late yielded significant increases in cardiac nitrite concentrations. CONCLUSIONS: Although there are some similarities between E2-early and E2-late treatments in relation to preservation of diastolic function and cardiac structure after OVX, the lusitropic potential of E2 is most consistent with late supplementation. The cardioprotective effects of E2-late are independent of blood pressure and may have occurred through regulation of cardiac biopterins and nitric oxide production.
Assuntos
Estradiol/administração & dosagem , Coração/efeitos dos fármacos , Ovariectomia , Animais , Biopterinas/metabolismo , Diástole/efeitos dos fármacos , Diástole/fisiologia , Estradiol/sangue , Feminino , Coração/anatomia & histologia , Coração/fisiopatologia , Hipertensão/complicações , Hipertensão/prevenção & controle , Miocárdio/patologia , Óxido Nítrico/biossíntese , Ratos , Ratos Endogâmicos Lew , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/prevenção & controleRESUMO
AIMS: GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman. METHODS AND RESULTS: Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 µg/kg/day), or vehicle was given subcutaneously to OVX rats from 13-15 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy. CONCLUSION: These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women.
Assuntos
Cardiotônicos/farmacologia , Ciclopentanos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Ovariectomia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Renina/genética , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Cardiotônicos/administração & dosagem , Linhagem Celular , Colágeno/metabolismo , Ciclopentanos/administração & dosagem , Ecocardiografia Doppler , Estrogênios/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Injeções Subcutâneas , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fenótipo , Quinolinas/administração & dosagem , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/metabolismo , Fatores de Tempo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
After oophorectomy, mRen2.Lewis rats exhibit diastolic dysfunction associated with elevated superoxide, increased cardiac neuronal nitric oxide synthase (nNOS) expression, and diminished myocardial tetrahydrobiopterin (BH4) content, effects that are attenuated with selective nNOS inhibition. BH4 is an essential cofactor of nNOS catalytic activity leading to nitric oxide production. Therefore, we assessed the effect of 4 wk BH4 supplementation on diastolic function and left ventricular (LV) remodeling in oophorectomized mRen2.Lewis rats compared with sham-operated controls. Female mRen2.Lewis rats underwent either bilateral ovariectomy (OVX) (n = 19) or sham operation (n = 13) at 4 wk of age. Beginning at 11 wk of age, OVX rats were randomized to receive either BH4 (10 mg/kg · d) or saline, whereas the sham rats received saline via sc mini-pumps. Loss of ovarian hormones reduced cardiac BH4 when compared with control hearts; this was associated with impaired myocardial relaxation, augmented filling pressures, increased collagen deposition, and thickened LV walls. Additionally, superoxide production increased and nitric oxide decreased in hearts from OVX compared with sham rats. Chronic BH4 supplementation after OVX improved diastolic function and attenuated LV remodeling while restoring myocardial nitric oxide release and preventing reactive oxygen species generation. These data indicate that BH4 supplementation protects against the adverse effects of ovarian hormonal loss on diastolic function and cardiac structure in mRen2.Lewis rats by restoring myocardial NO release and mitigating myocardial O2â» generation. Whether BH4 supplementation is a therapeutic option for the management of diastolic dysfunction in postmenopausal women will require direct testing in humans.
Assuntos
Biopterinas/análogos & derivados , Diástole/efeitos dos fármacos , Cardiopatias/fisiopatologia , Coração/fisiologia , Pós-Menopausa/metabolismo , Superóxidos/metabolismo , Animais , Biopterinas/administração & dosagem , Modelos Animais de Doenças , Feminino , Coração/efeitos dos fármacos , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Humanos , Miocárdio/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Ovariectomia , Pós-Menopausa/efeitos dos fármacos , Ratos , Ratos Endogâmicos Lew , Remodelação Ventricular/efeitos dos fármacosRESUMO
Fish oil (FO) mediates a number of cardioprotective benefits in patients with cardiovascular disease. In the absence of cardiovascular disease, however, the effects of FO on cardiac structure and function are not clear. In addition, it is not known if an effective dosing strategy for attenuating age-related cardiac dysfunction is also effective at limiting cognitive dysfunction. Therefore, we determined if 4 months of FO supplementation in aged rats would lessen age-related cardiac dysfunction while concomitantly preventing the cognitive decline that is normally observed in this population. The results indicate that FO initiated late in life modifies diastolic function in a small but positive way by attenuating the age-related increases in filling pressure, posterior wall thickness, and interstitial collagen without mitigating age-related deficits in memory or increases in brain inflammation. These data raise the possibility that FO supplementation for purposes of cardiac and brain protection may need to occur earlier in the life span.
Assuntos
Envelhecimento/fisiologia , Encéfalo/patologia , Diástole/efeitos dos fármacos , Gorduras Insaturadas na Dieta/farmacologia , Óleos de Peixe/farmacologia , Memória/efeitos dos fármacos , Envelhecimento/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Contagem de Células , Cognição/efeitos dos fármacos , Cognição/fisiologia , Diástole/fisiologia , Encefalite , Ácidos Graxos Ômega-3/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Visão Ocular/efeitos dos fármacos , Visão Ocular/fisiologiaRESUMO
OBJECTIVE: The loss of estrogen in mRen2.Lewis rats leads to an exacerbation of diastolic dysfunction. Because specific neuronal nitric oxide synthase (nNOS) inhibition reverses renal damage in the same model, we assessed the effects of inhibiting neuronal nitric oxide on diastolic function, left ventricular remodeling, and the components of the cardiac nitric oxide system in ovariectomized (OVX) and sham-operated mRen2.Lewis rats treated with N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO; 0.5 mg/kg per day for 28 d) or vehicle (saline). METHODS: Female mRen2.Lewis rats underwent either bilateral oophorectomy (OVX; n = 15) or sham operation (or surgical procedure) (sham; n = 19) at 4 weeks of age. Beginning at 11 weeks of age, the rats were randomized to receive either L-VNIO or vehicle. RESULTS: The surgical loss of ovarian hormones, particularly estrogen, led to exacerbated hypertension, impaired myocardial relaxation, diminished diastolic compliance, increased perivascular fibrosis, and increased relative wall thickness. The cardiac tetrahydrobiopterin-to-dihydrobiopterin levels were lower among OVX rats compared with sham-operated rats, and this altered cardiac biopterin profile was associated with enhanced myocardial superoxide production and decreased nitric oxide release. L-VNIO decreased myocardial reactive oxygen species production, increased nitrite concentrations, attenuated cardiac remodeling, and improved diastolic function. CONCLUSIONS: Impaired relaxation, diastolic stiffness, and cardiac remodeling were found among OVX mRen2.Lewis rats. A possible mechanism for this unfavorable cardiac phenotype may have resulted from a deficiency in available tetrahydrobiopterin and subsequent increase in nNOS-derived superoxide and reduction in nitric oxide synthase metabolites within the heart. Selective nNOS inhibition with L-VNIO attenuated cardiac superoxide production and limited remodeling, leading to improved diastolic function in OVX mRen2.Lewis rats.
Assuntos
Diástole/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca Diastólica/prevenção & controle , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico/metabolismo , Ornitina/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca Diastólica/metabolismo , Ornitina/farmacologia , Ovariectomia , Ratos , Ratos Endogâmicos LewRESUMO
INTRODUCTION: The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure. METHODS: Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age. RESULTS: Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler. CONCLUSION: Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ciclopentanos/farmacologia , Hipertensão/prevenção & controle , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Diástole , Ecocardiografia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Imuno-Histoquímica , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Endogâmicos Lew , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cloreto de Sódio na Dieta/administração & dosagemRESUMO
BACKGROUND: Hypertension and left ventricular (LV) hypertrophy often precede diastolic dysfunction and are risk factors for diastolic heart failure. Although pharmacologic inhibition of the renin-angiotensin system (RAS) improves diastolic function and functional capacity in hypertensive patients with LV hypertrophy, the effects of combination therapy with an angiotensin converting enzyme inhibitor (ACEi) and an angiotensin receptor blocker (ARB) are unclear. METHOD: We assessed the effects of the combined 10-week administration of lisinopril (10 mg/kg/ day, p.o.) and losartan (10 mg/kg/day, p.o.) (LIS/LOS) on diastolic function and LV structure in seven young (5 weeks), prehypertensive congenic mRen2.Lewis male rat, a model of tissue renin overexpression and angiotensin II (Ang II)-dependent hypertension compared to vehicle (VEH) treated (n = 7), age-matched rats. RESULTS: Systolic blood pressures were 64% lower with the combination therapy (p < 0.001), but there were no differences in heart rate or systolic function between groups. RAS inhibition increased myocardial relaxation, defined by tissue Doppler mitral annular descent (e') by 2.2 fold (p < 0.001). The preserved lusitropy in the LIS/LOS-treated rats was accompanied by a reduction in phospholamban-to-SERCA2 ratio (p < 0.001). Despite lower relative wall thicknesses (VEH: 1.56+/-0.17 versus LIS/LOS: 0.78+/-0.05) and filling pressures, defined by the transmitral Doppler-to-mitral annular descent ratio (E/e', VEH: 28.7+/-1.9 versus LIS/LOS: 17.96+/-1.5), no differences in cardiac collagen were observed. CONCLUSION: We conclude that the lusitropic benefit of early dual RAS blockade may be due to improved vascular hemodynamics and/or cardiac calcium handling rather than effects on extracellular matrix reduction.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Lisinopril/farmacologia , Losartan/farmacologia , Miocárdio/patologia , Renina/genética , Função Ventricular Esquerda/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Animais Congênicos , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Colágeno/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Ecocardiografia Doppler , Fibrose , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lisinopril/administração & dosagem , Losartan/administração & dosagem , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos Lew , Ratos Transgênicos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
The effects of chronic mild hypoxemia on the binding of angiotensin receptors in selected brain stem nuclei and reflex responses were studied in fetal sheep. Fetal and maternal catheters were placed at 120 days' gestation, and animals received intratracheal maternal administration of nitrogen (n = 16) or compressed air in controls (n = 19). Nitrogen infusion was adjusted to reduce fetal brachial artery PO(2) by 25% during 5 days. Spontaneous baroreflex sensitivity and spectral analysis of the pulse interval were analyzed during the 5 days hypoxemia period using 90 min of daily recording. Brains of control and hypoxemic animals were collected, and brain stem angiotensin receptor binding was studied by in vitro autoradiography at 130 days of gestation. After 5 days of hypoxemia, some animals in each group were submitted to one complete umbilical cord occlusion during 5 min. [(125)I]sarthran binding showed that chronic mild hypoxemia significantly increases angiotensin type 1 receptor, angiotensin type 2 receptor, and ANG-(1-7) angiotensin receptor binding sites in the nucleus tractus solitarius and dorsal motor nucleus of the vagus (P < 0.05). Hypoxemia induced lower baroreflex sensitivity and a higher low frequency-to-high frequency ratio in the fetus, consistent with a shift from vagal to sympathetic autonomic cardiac regulation. Cord occlusion to elicit a chemoreflex response induced a greater bradycardic response in hypoxemic fetuses (slope of the initial fall in heart rate; 11.3 +/- 1.9 vs. 6.4 +/- 1.2 beats x min(-1) x s(-1), P < 0.05). In summary, chronic mild hypoxemia increased binding of angiotensin receptors in brain stem nuclei, decreased spontaneous baroreflex gain, and increased chemoreflex responses to asphyxia in the fetus. These results suggest hypoxemia-induced alterations in brain stem mechanisms for cardiovascular control.
Assuntos
Barorreflexo/fisiologia , Tronco Encefálico/fisiopatologia , Feto/fisiopatologia , Expressão Gênica/fisiologia , Hipóxia/fisiopatologia , Receptores de Angiotensina/metabolismo , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Animais , Área Postrema/metabolismo , Asfixia/fisiopatologia , Gasometria , Pressão Sanguínea/fisiologia , Tronco Encefálico/metabolismo , Feminino , Sangue Fetal/química , Sangue Fetal/metabolismo , Feto/metabolismo , Frequência Cardíaca/fisiologia , Hemoglobinas/metabolismo , Concentração de Íons de Hidrogênio , Hipóxia/sangue , Hipóxia/metabolismo , Masculino , Bulbo/metabolismo , Núcleo Olivar/metabolismo , Gravidez , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Ovinos , Núcleo Solitário/metabolismoRESUMO
Accumulation of a large body of evidence during the past two decades testifies to the complexity of the renin-angiotensin system (RAS). The incorporation of novel enzymatic pathways, resulting peptides, and their corresponding receptors into the biochemical cascade of the RAS provides a better understanding of its role in the regulation of cardiovascular and renal function. Hence, in recent years, it became apparent that the balance between the two opposing effector peptides, angiotensin II and angiotensin-(1-7), may have a pivotal role in determining different cardiovascular pathophysiologies. Furthermore, our recent studies provide evidence for the functional relevance of a newly discovered rat peptide, containing two additional amino acid residues compared to angiotensin I, first defined as proangiotensin-12 [angiotensin-(1-12)]. This review focuses on angiotensin-(1-7) and its important contribution to cardiovascular function and growth, while introducing angiotensin-(1-12) as a potential novel angiotensin precursor.
Assuntos
Angiotensinas/metabolismo , Animais , Humanos , Sistema Renina-AngiotensinaRESUMO
A low expression of angiotensinogen in the heart has been construed as indicating a circulating uptake mechanism to explain the local effects of angiotensin II on tissues. The recent identification of angiotensin-(1-12) in an array of rat organs suggests this propeptide may be an alternate substrate for local angiotensin production. To test this hypothesis, tissues from 11-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (n = 14) were stained with purified antibodies directed to the COOH terminus of angiotensin-(1-12). Robust angiotensin-(1-12) staining was predominantly found in ventricular myocytes with less staining found in the medial layer of intracoronary arteries and vascular endothelium. In addition, angiotensin-(1-12) immunoreactivity was present in the proximal, distal, and collecting renal tubules within the deep cortical and outer medullary zones in both strains. Preadsorption of the antibody with angiotensin-(1-12) abolished staining in both tissues. Corresponding tissue measurements by radioimmunoassay showed 47% higher levels of angiotensin-(1-12) in the heart of SHR compared with WKY rats (P < 0.05). In contrast, renal angiotensin-(1-12) levels were 16.5% lower in SHR compared with the WKY rats (P < 0.05). This study shows for first time the localization of angiotensin-(1-12) in both cardiac myocytes and renal tubular components of WKY and SHR. In addition, we show that increased cardiac angiotensin-(1-12) concentrations in SHR is associated with a small, but statistically significant, reduction in renal angiotensin-(1-12) levels.
Assuntos
Angiotensinogênio/análise , Hipertensão/metabolismo , Túbulos Renais/química , Miocárdio/química , Fragmentos de Peptídeos/análise , Angiotensinogênio/imunologia , Animais , Especificidade de Anticorpos , Modelos Animais de Doenças , Imuno-Histoquímica/métodos , Masculino , Miócitos Cardíacos/química , Fragmentos de Peptídeos/imunologia , Radioimunoensaio , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Identification of angiotensin-(1-12) as an intermediate precursor derived directly from angiotensinogen led us to explore whether the heart has the capacity to process angiotensin-(1-12) into biologically active angiotensin peptides. The generation of angiotensin I, angiotensin II, and angiotensin-(1-7) from exogenous angiotensin-(1-12) was evaluated in the effluent of isolated perfused hearts mounted on a Langendorff apparatus in three normotensive and two hypertensive strains: Sprague-Dawley, Lewis, congenic mRen2.Lewis, Wistar-Kyoto, and spontaneously hypertensive rats. Hearts were perfused with Krebs solution for 60 min before and after the addition of angiotensin-(1-12) (10 nmol/l). Angiotensin-(1-12) caused the rapid appearance of both angiotensin I and angiotensin II in the perfusate that peaked between 30 and 60 min of recirculation. Production of angiotensin-(1-7) from exogenous angiotensin-(1-12) rose steadily over the course of the 60-min experiment. These data directly demonstrate that angiotensin-(1-12) is a substrate for the formation of angiotensin peptides in cardiac tissue. This finding further suggests that this angiotensinogen-derived product is a previously unrecognized important precursor peptide to the renin-angiotensin system cascade.
Assuntos
Angiotensinogênio/metabolismo , Angiotensinas/metabolismo , Hipertensão/metabolismo , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Sistema Renina-Angiotensina , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Masculino , Perfusão , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Renina/genética , Renina/metabolismo , Fatores de TempoRESUMO
Fifty years since their introduction, thiazide diuretics are established as first-line therapy in the treatment of hypertension. Because the dosing profile for thiazide agents lessened, the mechanism responsible for the blood pressure lowering effect may lie outside their diuretic properties. We evaluated the mechanism driving blood pressure reductions in spontaneously hypertensive rats (SHR) and normotensive WKY by examining the effects of low-dose hydrochlorothiazide (HCTZ) administration on renin-angiotensin system (RAS) components. The 7-day, 1.5 mg/kg/day HCTZ did not change systolic pressure in WKY, but decreased SBP by 41 +/- 2 mm Hg (p < 0.0001) in SHR. This reduction was independent of increases in water intake, urine output, or alterations in electrolyte excretion. HCTZ significantly increased the plasma concentrations of angiotensin I (Ang I) and angiotensin II (Ang II) in both WKY and SHR while reducing angiotensin converting enzyme (ACE) activity and the Ang II/Ang I ratio (17.1 +/- 2.9 before versus 10.3 +/- 2.9 after, p < 0.05) only in SHR. HCTZ increased cardiac ACE2 mRNA and activity, and neprilysin mRNA in WKY, but not SHR. Conversely in SHR, ACE2 activity was decreased and aside from a 75% increase in AT(1) mRNA in the HCTZ-treated SHR, the expression of the other variables remained unaltered. Measures of cardiac mas receptor mRNA showed no changes in response to treatment in both strains, although cardiac mas mRNA was significantly lower in untreated SHR. These data, which document for the first time the effect of low-dose thiazide on the activity of the ACE2/Ang-(1-7)/mas-receptor axis, suggest that the opposing arm of the system does not substantially contribute to the antihypertensive effect of low-dose thiazides in SHR.
RESUMO
INTRODUCTION: The presence of Angiotensin (1-7) (Ang 1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters as well as the influence of Ang (1-7) on membrane potential, impulse propagation and cardiac excitability were investigated. METHODS: Histology and immunochemistry were used to demonstrate the presence of Ang (1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters. Measurements of transmembrane potentials, conduction velocity and refractoriness were made using conventional intracellular microelectrodes. The influence of Ang (1-7) on sodium pump current was investigated in voltageclamped myocytes isolated from the ventricle. RESULTS: The results indicated the presence of Ang (1-7) and ACE 2 in myocytes of cardiomyopathic hamsters. Moreover,Ang (1-7) (10(-8) M) hyperpolarised the heart cell, increased the conduction velocity, and reduced transiently the action potential duration. The cardiac refractoriness was also increased by the heptapeptide, an effect in part reduced by an inhibitor of mas receptor. These findings indicate that Ang (1-7) has important antiarrhythmic properties. However, the beneficial effects of Ang (1-7) are dose-dependent because at higher concentration (10(-7) M) the heptapeptide elicited an appreciable increase of action potential duration and early-after depolarisations. Since losartan (10(-7) M) did not counteract this effect of the high dose of the heptapeptide, it is possible to conclude that activation of AT(1)-receptors is not involved in this effect of Ang (1-7). To investigate the mechanism of the hyperpolarising action of Ang (1-7) the influence of the heptapeptide on the sodium potassium pump current was studied in myocytes isolated from the ventricle of cardiomyopathic hamsters. The peak pump current density was measured under voltage clamp using the whole cell configuration. The results indicated that Ang (1-7) (10(-8) M) enhanced the electrogenic sodium pump, an effect suppressed by ouabain (10(-7) M). CONCLUSIONS: Ang (1-7) has beneficial effects on the failing heart by activating the sodium pump, hyperpolarising the cell membrane and increasing the conduction velocity. These effects as well as the increment of refractoriness indicate that Ang (1-7) has antiarrhythmic properties. At higher concentrations (10(-7) M), however, the heptapeptide induced early-after depolarisations which leads to the conclusion that an optimal generation of Ang (1-7) must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias.
Assuntos
Angiotensina I/uso terapêutico , Cardiomiopatias/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Coração/fisiopatologia , Potenciais da Membrana/fisiologia , Fragmentos de Peptídeos/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Cricetinae , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Imuno-Histoquímica , Potenciais da Membrana/efeitos dos fármacos , Miocárdio/patologia , Canais de Sódio/efeitos dos fármacosRESUMO
The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a backcross of the hypertensive (mRen2)27 transgenic rat with normotensive Lewis rats, provides a new model by which primary hypertension can be studied without the genetic variability found in the original strain. The purpose of this study was to characterize the Lew.Tg(mRen2) rats by dually investigating the effects of type 1 angiotensin II (ANG II) receptor (AT(1)) blockade and angiotensin-converting enzyme (ACE) activity inhibition on the ANG-(1-7)/ACE2 axis of the renin-angiotensin system in this new hypertensive model. The control of blood pressure elicited by 12-day administration of either lisinopril (mean difference change = 92 +/- 2, P < 0.05) or losartan (mean difference change = 69 +/- 2, P < 0.05) was associated with 54% and 33% increases in cardiac ACE2 mRNA and 54% and 43% increases in cardiac ACE mRNA, respectively. Lisinopril induced a 3.1-fold (P < 0.05) increase in renal cortical expression of ACE2, whereas losartan increased ACE2 mRNA 3.5-fold (P < 0.05). Both treatment regimens increased renal ACE mRNA 2.6-fold (P < 0.05). The two therapies augmented ACE2 protein activity, as well as increased cardiac and renal AT(1) receptor mRNAs. ACE inhibition reduced plasma ANG II levels (81%, P < 0.05) and increased plasma ANG-(1-7) (265%, P < 0.05), whereas losartan had no effect on the peptides. In contrast with what had been shown in normotensive rats, ACE inhibition decreased renal ANG II excretion and transiently decreased ANG-(1-7) excretion, whereas losartan treatment was associated with a consistent decrease in ANG-(1-7) urinary excretion rates. In response to the treatments, the expression of both renal cortical renin and angiotensinogen mRNAs was significantly augmented. The paradoxical effects of blockade of ANG II synthesis and activity on urinary excretion rates of the peptides and plasma angiotensins levels suggest that, in Lew.Tg(mRen2) congenic rats, a failure of compensatory ACE2 and ANG-(1-7)-dependent vasodepressor mechanisms may contribute both to the development and progression of hypertension driven by increased formation of endogenous ANG II.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Hipertensão Renal/genética , Modelos Genéticos , Peptidil Dipeptidase A/efeitos dos fármacos , Renina/genética , Angiotensina I/sangue , Angiotensina I/urina , Angiotensina II/antagonistas & inibidores , Angiotensina II/sangue , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Animais Congênicos , Animais Geneticamente Modificados , Cruzamentos Genéticos , Hipertensão Renal/metabolismo , Cinética , Lisinopril/farmacologia , Losartan/farmacologia , Masculino , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/urina , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Fatores de TempoRESUMO
Angiotensin-converting enzyme 2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the COOH-terminus of its substrates. Because ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1-7), this has changed our overall perspective about the classical view of the renin angiotensin system in the regulation of hypertension and heart and renal function, because it represents the first example of a feedforward mechanism directed toward mitigation of the actions of angiotensin II. This paper reviews the new data regarding the biochemistry of angiotensin-(1-7)-forming enzymes and discusses key findings such as the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1-7) in the control of the circulation.
Assuntos
Angiotensina I/metabolismo , Bioquímica/tendências , Pressão Sanguínea , Carboxipeptidases/metabolismo , Sistema Cardiovascular/fisiopatologia , Hipertensão/fisiopatologia , Fragmentos de Peptídeos/metabolismo , Sistema Renina-Angiotensina , Enzima de Conversão de Angiotensina 2 , Animais , Retroalimentação , Humanos , Infarto do Miocárdio/fisiopatologia , Peptidil Dipeptidase ARESUMO
1. The present review provides an update on evidence of the neurotransmitter pathways and location of receptors within the nucleus tractus solitarii (NTS) mediating the baroreflex and other haemodynamic actions of angiotensin (Ang) II. 2. A series of studies suggests a significant role for substance P in the acute cardiovascular and carotid sinus chemoreceptor facilitatory actions of AngII in the NTS. The use of antisense oligonucleotides to AT1 receptors indicates both pre- and post-synaptic AngII receptors are likely to be involved in these actions. 3. With respect to baroreceptor reflex actions, it is clear that endogenous AngII impairs the gain for operation of the baroreceptor reflex, because AT1 receptor antagonists facilitate reflex function. This effect is either independent of substance P or involves inhibition of release. Moreover, initial data obtained using antisense oligonucleotides to AT1 receptors suggest that, in the NTS, the effect of endogenous AngII on the baroreceptor reflex is mainly due to presynaptic actions on vagal or carotid sinus afferent fibres. In contrast, the level of endogenous AngII within the NTS appears to have variable effects on activation of cardiopulmonary vagal afferent fibres by phenylbiguanide. These results indicate a divergence of effects of AngII on reflexes evoked by these two different types of sensory input. 4. Use of transgenic rats with alterations in brain angiotensin peptides allowed us to assess the effect of long-term alterations in brain Ang peptides on reflex function. We studied (mRen2)27 transgenic rats (TGR(mRen2)) with high brain medulla AngII levels and transgenic rats with angiotensinogen (Aogen) antisense linked to glial fibrillary acidic protein promoter (TGR(ASrAogen)) with greatly reduced brain Aogen. The reflex evoked by activation of cardiac vagal chemosensitive afferent fibres was enhanced in TGR(ASrAogen), whereas the baroreceptor reflex control of heart rate was attenuated in TGR(mRen2), further confirming a divergence of effects of AngII on these two sensory modalities. 5. The overall results are consistent with a sustained inhibitory effect of AngII on the baroreceptor reflexes, with dose-dependent or activation-dependent effects on cardiac vagal afferent fibre activation. Moreover, alterations in substance P pathways may contribute to the actions of AngII on reflex function.