Terapia Trombolítica em Octogenários com Embolia Pulmonar Aguda / Thrombolytic Therapy in Octogenarians with Acute Pulmonary Embolism

Resumo Fundamento Apesar da grande proporção de octogenários com embolia pulmonar aguda, há pouca informação indicando a estratégia de manejo ideal, especialmente medidas terapêuticas, como a terapia lítica. Objetivos O número de pacientes idosos diagnosticados com embolia pulmonar aguda aumenta constantemente. Porém, o papel do tratamento trombolítico não está claramente definido entre os octogenários. Nosso objetivo é avaliar a efetividade da terapia lítica em pacientes octogenários diagnosticados com embolia pulmonar. Métodos Cento e quarenta e oito indivíduos (70,3% de mulheres, n=104) com mais de 80 anos foram incluídos no estudo. Os pacientes foram divididos em dois grupos: tratamento trombolítico versus não-trombolítico. As taxas de mortalidade hospitalar e episódios de sangramento foram definidos como desfechos do estudo. Valor de p <0,05 foi considerado como estatisticamente significativo. Resultados A mortalidade hospitalar reduziu significativamente no grupo trombolítico em comparação ao não-trombolítico (10,5% vs. 24,2%; p=0,03). Episódios de sangramento menores foram mais comuns no braço que recebeu o tratamento trombolítico, mas grandes hemorragias não diferiram entre os grupos (35,1% vs. 13,2%, p<0,01; 7% vs. 5,5% p=0,71, respectivamente). O escore de PESI alto (OR: 1,03 IC95%; 1,01-1,04 p<0,01), a terapia trombolítica (OR: 0,15 IC95%; 0,01-0,25, p< 0,01) e níveis altos de troponina (OR: 1,20 IC95%; 1,01-1,43, p=0,03) estiveram independentemente associados a taxas de mortalidade hospitalar na análise de regressão multivariada. Conclusão A terapia trombolítica esteve associada à mortalidade hospitalar reduzida em detrimento do aumento geral das complicações de sangramento em octogenários.

Abstract Background Despite the high proportion of octogenarians with acute pulmonary embolism, there is little information indicating the optimal management strategy, mainly therapeutic measures, such as lytic therapy. Objectives The number of elderly patients diagnosed with acute pulmonary embolism increases constantly. However, the role of thrombolytic treatment is not clearly defined among octogenarians. Our objective is to evaluate the effectiveness of lytic therapy in octogenarian patients diagnosed with pulmonary embolism. Methods One hundred and forty eight subjects (70.3% women, n=104) aged more than eighty years were included in the study. The patients were divided in two groups: thrombolytic versus non-thrombolytic treatment. In-hospital mortality rates and bleeding events were defined as study outcomes. P-value <0.05 was considered as statistical significance. Results In-hospital mortality decreased significantly in the thrombolytic group compared to the non-thrombolytic group (10.5% vs. 24.2% p=0.03). Minor bleeding events were more common in the arm that received thrombolytic treatment, but major hemorrhage did not differ between the groups (35.1% vs. 13.2%, p<0.01; 7% vs. 5.5% p=0.71, respectively). High PESI score (OR: 1.03 95%CI; 1.01-1.04 p<0.01), thrombolytic therapy (OR: 0.15 95%CI; 0.01-0.25, p< 0.01) and high troponin levels (OR: 1.20 95%CI; 1.01-1.43, p=0.03) were independently associated with in-hospital mortality rates in the multivariate regression analysis. Conclusion Thrombolytic therapy was associated with reduced in-hospital mortality at the expense of increased overall bleeding complications in octogenarians.

O Papel dos Níveis Séricos de ANP na Perda de Peso, Risco Cardiometabólico e Composição Corporal de Adolescentes com Obesidade Submetidos a Terapia Interdisciplinar / The Role of ANP Level Response in Interdisciplinary Weight Loss Therapy on Cardiometabolic Risk and Body Composition in Adolescents with Obesity

Resumo Fundamento A ação do peptídeo natriurético atrial (ANP) na natriurese, diurese e vasodilatação, resistência à insulina, fígado, rim e tecido adiposo pode contribuir para o desenvolvimento metabólico e cardiovascular saudável. Embora o nível circulante de ANP seja reduzido em pacientes com obesidade, sua resposta à perda de peso ainda é pouco explorada em populações pediátricas. Objetivo Avaliar os efeitos das variações do ANP em resposta à intervenção interdisciplinar para perda de peso na Síndrome Metabólica (SMet) e nos riscos cardiometabólicos em adolescentes com obesidade. Métodos 73 adolescentes com obesidade participaram de uma terapia interdisciplinar para perda de peso de 20 semanas, incluindo uma abordagem clínica, nutricional, psicológica e de exercícios físicos. A composição corporal, análises bioquímicas e pressão sanguínea foram avaliadas. A SMet foi classificada de acordo com a Federação Internacional de Diabetes (IDF) (2007). Após o tratamento, os voluntários foram divididos de acordo com os níveis de plasma do ANP aumento (n=31) ou ANP redução (n=19). Resultados Ambos os grupos apresentaram redução significativa de peso corporal, índice de massa corporal (IMC) e circunferências de cintura, pescoço e quadril (CC, CP e CQ, respectivamente), e aumento da massa livre de gordura (MLG). É interessante observar que houve uma redução significativa na gordura corporal, na razão de TG/HDL-c e na prevalência de SMet (de 23% para 6%) somente no grupo com ANP aumento. Conclusão Este estudo sugere que o aumento nos níveis séricos de ANP após a terapia para perda de peso pode estar associado a melhorias nos riscos cardiometabólicos e na prevalência reduzida de SMet em adolescentes com obesidade.

Abstract Background The action of atrial natriuretic peptide (ANP) on natriuresis, diuresis and vasodilatation, insulin resistance, liver, kidney, and adipose tissue may contribute to the healthy metabolic and cardiovascular development. Even though the circulating level of ANP is reduced in patients with obesity, its response to weight loss remains poorly explored in pediatric populations. Objective To evaluate the effects of ANP variations in response to interdisciplinary weight loss intervention on metabolic syndrome (MetS) and cardiometabolic risks in adolescents with obesity. Methods 73 adolescents with obesity attended a 20-week clinical interdisciplinary weight loss therapy including clinical, nutritional, psychological and exercise training approach. Body composition, biochemical analyses and blood pressure were evaluated. MetS was classified according to the International Diabetes Federation (IDF) (2007). After the treatment, volunteers were divided according to Increasing (n=31) or Decreasing (n=19) ANP plasma levels. Results Both groups present significant reduction of body weight, Body Mass Index (BMI), waist, neck and hip circumferences (WC, NC and HC, respectively) and increasing fat-free mass (FFM). Interestingly, a significant reduction in body fat, TG/HDL-c ratio and MetS prevalence (from 23% to 6%) was observed in the Increased ANP group only. Conclusion This study suggests that an increase in ANP serum levels after weight loss therapy could be associated with improvements in cardiometabolic risks and the reduced prevalence of MetS in adolescents with obesity.

Ghrelin improves the fine structure of atrial natriuretic factor (ANF) granules and intercalated disc junctions in experimentally-induced myocardial infarction in rats / La grelina mejora las estructuras finas de los gránulos de factor natriurético atrial (ANF) y las uniones intercaladas de disco en el infarto de miocardio inducido experimentalmente en ratas

Ghrelin is a novel growth hormone-releasing peptide administered to treat myocardial infarction (MI). However, the underlying mechanism of its protective effects against MI remains unclear. A total of sixty healthy Sprague Dawley male rats were included. The first one is the sham-operated control group were the rats that underwent the same surgical used to induce MI but without tying the left anterior descending coronary artery (LAD) and received normal saline (0.5 ml) as vehicle; the second MI model group were rats with LAD ligation and received normal saline (0. 5 ml) and the third one is MI+ghrelin group were rats that were exposed to surgery to induce MI but received ghrelin (100 µ/kg, orally, 2x/day). At the end of the experiment after 21 days post-MI, rats were sacrificed and processed for ultrastructural demonstration. Our experiment showed that ghrelin inhibited cardiomyocyte apoptosis. Concomitant administration of ghrelin with MI treated rats of this study appeared to show a considerable protection of the atrial tissues. This study revealed that the sarcoplasm was occupied by normal myofibrils with clear striations and others appeared with minor disruption. Normal distribution of atrionatriuretic factor (ANF) granules and well preserved mitochondrial integrity (preserved cristae, normal size and shape), nucleus chromatin arrangement and striated pattern of clear bands (Z and H) compared to the MI group. Intact intercalated disc with clear identification of fully formed fascia adherence and desmosomes with a reconstruction of gap junction (nexus) was also noticed. Atrial myocytes after myocardial infarction is often associated with subsequent heart failure, which could lead to a fatal outcome. In a rat model of experimental myocardial infarction, peripheral ghrelin administration attenuated myocyte dysfunction, well-preserved desmosome, adherent and gap junction of the intercalated disc and normally distributed ANF granules.

La grelina es un nuevo péptido liberador de hormona de crecimiento administrado para tratar el infarto de miocardio (IM). Sin embargo, el mecanismo subyacente de sus efectos protectores contra el IM aún no se conocen. Se incluyeron un total de 60 ratas macho Sprague Dawley saludables. En el grupo control se incluyeron ratas que fueron sometidas a una cirugía utilizada para inducir el IM, pero sin ligar la arteria coronaria descendente anterior izquierda (ACDAI) y recibieron suero fisiológico normal (0,5 ml) como vehículo; el segundo grupo modelo de IM fueron ratas con ligadura de ACDAI y recibieron suero fisiológico normal (0,5 ml); el tercer grupo estuvo formado por ratas con IM + grelina, expuestas a la cirugía para inducir IM pero luego recibieron grelina (100 m/kg, oralmente, 2x/día). Al final del experimento, 21 días después del infarto de miocardio, los animales fueron sacrificados y procesados para el estudio ultraestructural. Nuestro experimento mostró que la grelina inhibe la apoptosis de los cardiomiocitos. La administración concomitante de grelina en ratas con IM parece indicar una protección considerable de los tejidos atriales. Además, el estudio reveló que el sarcoplasma estaba ocupado por miofibrillas normales con estriaciones claras y otras con una alteración menor. Se encontró una distribución normal de los gránulos del factor natriurético atrial (FNA) e integridad mitocondrial bien conservada (crestas conservadas, tamaño y forma normales), disposición de la cromatina del núcleo y patrón estriado de bandas claras (Z y H) en comparación con el grupo IM. También se observó un disco intercalado intacto con una clara identificación de la adherencia de la fascia completamente formada y desmosomas con una reconstrucción de la unión gap (nexo). Los miocitos atriales, después de un infarto de miocardio, a menudo se asocian con insuficiencia cardíaca posterior, que podría conducir a un desenlace fatal. En un modelo de rata de infarto de miocardio experimental, la administración de grelina periférica atenuó la disfunción de miocitos, con conservación del desmosoma, adherencia y unión de la brecha del disco intercalado y una distribución normal de los los gránulos de FNA.

Etanercept protects rat cardiomyocytes against hypertrophy by regulating inflammatory cytokines secretion and cell apoptosis

We aimed to investigate the effect of etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, on rat cardiomyocyte hypertrophy and its underlying mechanism. Primary neonatal rat cardiomyocytes were isolated from Sprague-Dawley rats. The model of rat cardiomyocyte hypertrophy was induced by endothelin, and then treated with different concentrations of etanercept (1, 10, and 50 μM). After treatment, cell counts, viability and cell apoptosis were evaluated. The mRNA levels of myocardial hypertrophy marker genes, including atrial natriuretic factor (ANF), matrix metalloproteinase (MMP)-9 and MMP-13, were detected by qRT-PCR, and the expressions of apoptosis-related proteins (Bcl-2 and Bax) were measured by western blotting. The protein levels of transforming growth factor-β1 (TGF-β1), interleukin (IL)-1β, IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 (CT-1) were determined using enzyme linked immunosorbent assay (ELISA) kits. In the present study, TNF-α level in cardiomyocytes with hypertrophy was significantly enhanced (P<0.05). Compared to the model group, cell number and viability were significantly increased and ratio of apoptotic cells was reduced by etanercept (P<0.05, P<0.01, or P<0.001). In addition, etanercept remarkably reduced the mRNA levels of ANF, MMP-9 and MMP-13, inhibited the expression of Bax, and increased the expression of Bcl-2 compared to the model group (P<0.05). ELISA results further showed that etanercept lowered the levels of IL-1β, IL-6, LIF and CT-1 but not TGF-β1 compared to the model group (P<0.05). Etanercept may protect rat cardiomyocytes from hypertrophy by inhibiting inflammatory cytokines secretion and cell apoptosis.

Overexpression of myeloid differentiation protein 88 in mice induces mild cardiac dysfunction, but no deficit in heart morphology

Cardiac remodeling involves changes in heart shape, size, structure, and function after injury to the myocardium. The proinflammatory adaptor protein myeloid differentiation protein 88 (MyD88) contributes to cardiac remodeling. To investigate whether excessive MyD88 levels initiate spontaneous cardiac remodeling at the whole-organism level, we generated a transgenic MyD88 mouse model with a cardiac-specific promoter. MyD88 mice (male, 20-30 g, n=∼80) were born at the expected Mendelian ratio and demonstrated similar morphology of the heart and cardiomyocytes with that of wild-type controls. Although heart weight was unaffected, cardiac contractility of MyD88 hearts was mildly reduced, as shown by echocardiographic examination, compared with wild-type controls. Moreover, the cardiac dysfunction phenotype was associated with elevation of ANF and BNP expression. Collectively, our data provide novel evidence of the critical role of balanced MyD88 signaling in maintaining physiological function in the adult heart.

El corazón endocrino y el proceso inflamatorio / [The endocrine heart and inflammation].

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.

The analysis of pericardial fluid in forensic practice / 法医学杂志

Pericardial fluid is a kind of serous fluid in pericardial cavity. Because blood undergoes postmortem changes such as autolysis and putrefaction, vitreous humor is limited,cerebrospinal fluid is easily mixed with blood, pericardial fluid, on the other hand, exists in a closed cavity and can be hardly contaminated by postmortem changes, and also is easily obtained. Pericardial fluid not only plays an important role in clinic practice, but also is widely applicable in forensic practice. This paper briefly presented the properties of pericardial fluid and its clinical significance. It reviewed biochemical changes in decedents died of heart diseases, drowning and asphyxia, and explored the significance in medico-legal investigation. Moreover, application of pericardial fluid in forensic serology, forensic toxicological analysis and other fields were also discussed. Pericardial fluid analysis may provide important information for determination of the cause of death with further investigation concerning forensic applicability of pericardial fluid.

The application of biochemical indexes detecting in sudden cardiac death in forensic autopsy / 法医学杂志

Sudden cardiac death(SCD) from early myocardial ischemia is often lack of typically morphological findings and clinical manifestation, thus cases of SCD may be suspected as criminal cases. It is necessary to clarify the cause of death, which is significance for medico-legal investigation. This article reviewed the latest advancement in the studies on the application of inorganic ions, CK-MB, cTn, ANP and BNP for certification of death from SCD in order to provide a practical way for diagnosis of SCD in forensic pathology.

Different Regulation of Atrial ANP Release through Neuropeptide Y2 and Y4 Receptors

Neuropeptide Y (NPY) receptors are present in cardiac membranes. However, its physiological roles in the heart are not clear. The aim of this study was to define the direct effects of pancreatic polypeptide (PP) on atrial dynamics and atrial natriuretic peptide (ANP) release in perfused beating atria. Pancreatic polypeptides, a NPY Y4 receptor agonist, decreased atrial contractility but was not dose-dependent. The ANP release was stimulated by PP in a dose-dependent manner. GR 23118, a NPY Y4 receptor agonist, also increased the ANP release and the potency was greater than PP. In contrast, peptide YY (3-36) (PYY), an NPY Y2 receptor agonist, suppressed the release of ANP with positive inotropy. NPY, an agonist for Y1, 2, 5 receptor, did not cause any significant changes. The pretreatment of NPY (18-36), an antagonist for NPY Y3 receptor, markedly attenuated the stimulation of ANP release by PP but did not affect the suppression of ANP release by PYY. BIIE0246, an antagonist for NPY Y2 receptor, attenuated the suppression of ANP release by PYY. The responsiveness of atrial contractility to PP or PYY was not affected by either of the antagonists. These results suggest that NPY Y4 and Y2 receptor differently regulate the release of atrial ANP.

Dosagem do fator natriurético atrial em pacientes pediátricos submetidos à ventilaçäo pulmonar mecânica / Dosage of atrial natriuretic peptide in pediatric patients submitted to mechanical ventilation

OBJETIVOS: Os objetivos deste trabalho foram verificar se existe alteraçäo na secreçäo do fator natriurético atrial (FNA) em crianças submetidas à ventilaçäo pulmonar mecânica e se essas possíveis alterações levariam à modificações no débito urinário e na excreçäo urinária de sódio. METODOLOGIA: Estudo prospectivo, realizado em uma Unidade de Cuidados Intensivos Pediátricos Terciária, em nove crianças submetidas à ventilaçäo pulmonar mecânica para recuperaçäo anestésica, exceto em uma que sofreu traumatismo cranioencefálico näo-cirúrgico. O período de estudo foi de Setembro de 1995 a Março de 1996. Aguardava-se pelo menos três horas do início da ventilaçäo pulmonar mecânica e entäo colhia-se amostra de sangue para dosagem de fator natriurético atrial, gasometria arterial, glicemia, creatinina e eletrólitos. Coletava-se ainda urina durante 6 horas para a verificaçäo do débito urinário e da concentraçäo de sódio. Depois da extubaçäo, aguardava-se por um período de 15 a 30 minutos e colhia-se sangue e urina para as mesmas dosagens realizadas anteriormente. A comparaçäo estatística foi feita pelo teste näo-paramétrico de Wilcoxon Signed Rank, sendo o nível de significância de 0,05. RESULTADOS: O fator natriurético atrial mostrou uma tendência ao aumento quando a ventilaçäo pulmonar mecânica foi retirada (p= 0,0547). O débito urinário e a natriurese näo se alteraram com a ventilaçäo pulmonar mecânica. CONCLUSÕES: A tendência ao aumento do fator natriuretico atrial ocorreu provavelmente por diminuiçäo da pressäo intratorácica. A reposiçäo volêmica no trans-operatório pode ter influenciado no débito urinário e na natriurese. Em pacientes submetidos à ventilaçäo pulmonar mecânica por períodos prolongados, com altos parâmetros de pressäo inspiratória e pressäo expiratória final positiva, seria interessante a dosagem do fator natriurético atrial e se esse se encontrasse diminuído, seria uma indicaçäo para o seu uso

Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection

The release of adrenocorticotropin (ACTH) from the corticotrophs is controlled principally by vasopressin and corticotropin-releasing hormone (CRH). Oxytocin may augment the release of ACTH under certain conditions, whereas atrial natriuretic peptide acts as a corticotropin release-inhibiting factor to inhibit ACTH release by direct action on the pituitary. Glucocorticoids act on their receptors within the hypothalamus and anterior pituitary gland to suppress the release of vasopressin and CRH and the release of ACTH in response to these neuropeptides. CRH neurons in the paraventricular nucleus also project to the cerebral cortex and subcortical regions and to the locus ceruleus (LC) in the brain stem. Cortical influences via the limbic system and possibly the LC augment CRH release during emotional stress, whereas peripheral input by pain and other sensory impulses to the LC causes stimulation of the noradrenergic neurons located there that project their axons to the CRH neurons stimulating them by alpha-adrenergic receptors. A muscarinic cholinergic receptor is interposed between the alpha-receptors and nitric oxidergic interneurons which release nitric oxide that activates CRH release by activation of cyclic guanosine monophosphate, cyclooxygenase, lipoxygenase and epoxygenase. Vasopressin release during stress may be similarly mediated. Vasopressin augments the release of CRH from the hypothalamus and also augments the action of CRH on the pituitary. CRH exerts a positive ultrashort loop feedback to stimulate its own release during stress, possibly by stimulating the LC noradrenergic neurons whose axons project to the paraventricular nucleus to augment the release of CRH.

Relationship between the actions of atrial natriuretic peptide (ANP), guanylin and uroguanylin on the isolated kidney

Guanylin and uroguanylin are peptides that bind to and activate guanylate cyclase C and control salt and water transport in many epithelia in vertebrates, mimicking the action of several heat-stable bacteria enterotoxins. In the kidney, both of them have well-documented natriuretic and kaliuretic effects. Since atrial natriuretic peptide (ANP) also has a natriuretic effect mediated by cGMP, experiments were designed in the isolated perfused rat kidney to identify possible synergisms between ANP, guanylin and uroguanylin. Inulin was added to the perfusate and glomerular filtration rate (GFR) was determined at 10-min intervals. Sodium was also determined. Electrolyte dynamics were measured by the clearance formula. Guanylin (0.5 µg/ml, N = 12) or uroguanylin (0.5 µg/ml, N = 9) was added to the system after 30 min of perfusion with ANP (0.1 ng/ml). The data were compared at 30-min intervals to a control (N = 12) perfused with modified Krebs-Hanseleit solution and to experiments using guanylin and uroguanylin at the same dose (0.5 µg/ml). After previous introduction of ANP in the system, guanylin promoted a reduction in fractional sodium transport (TNa+, P<0.05) (from 78.46 + or - 0.86 to 64.62 = or - 1.92, 120 min). In contrast, ANP blocked uroguanylin-induced increase in urine flow (from 0.21 = or - 0.01 to 0.15 + or - 0.007 ml g-1 min-1, 120 min, P<0.05) and the reduction in fractional sodium transport (from 72.04 + or - 0.86 to 85.19 + or - 1.48, TNa+, at 120 min of perfusion, P<0.05). Thus, the synergism between ANP + guanylin and the antagonism between ANP + uroguanylin indicate the existence of different subtypes of receptors mediating the renal actions of guanylins

A liver metalloendopeptidase which degrades the circulating hypotensive peptide hormones bradykinin and atrial natriuretic peptide

A new metalloendopeptidase was purified to apparent homogeneity from a homogenate of normal human liver using successive steps of chromatography on DEAE-cellulose, hydroxyapatite and Sephacryl S-200. The purified enzyme hydrolyzed the Pro7-Phe8 bond of bradykinin and the Ser25-Tyr26 bond of atrial natriuretic peptide. No cleavage was produced in other peptide hormones such as vasopressin, oxytocin or Met- and Leu-enkephalin. This enzyme activity was inhibited by 1 mM divalent cation chelators such as EDTA, EGTA and o-phenanthroline and was insensitive to 1 µM phosphoramidon and captopril, specific inhibitors of neutral endopeptidase (EC 3.4.24.11) and angiotensin-converting enzyme (EC 3.4.15.1), respectively. With Mr 85 kDa, the enzyme exhibits optimal activity at pH 7.5. The high affinity of this endopeptidase for bradykinin (Km = 10 µM) and for atrial natriuretic peptide (Km = 5 µM) suggests that it may play a physiological role in the inactivation of these circulating hypotensive peptide hormones

Augmented expression of cardiac atrial natriuretic peptide system in hypertensive rats

The present study was aimed at investigating the regulation of atrial natriuretic peptide (ANP) system in association with either enhanced or attenuated activity of the renin-angiotensin system (RAS). The cardiac tissue mRNA and peptide levels of ANP were measured in rats with two-kidney, one clip (2K1C) or deoxycorticosterone acetate (DOCA)-salt hypertension. Plasma renin concentration was increased in 2K1C hypertension along with increases of renin mRNA and protein contents in the clipped kidney. On the contrary, it was suppressed in DOCA-salt hypertension along with decreases of renin mRNA and protein contents in the remaining kidney. The plasma ANP concentration was similarly increased in both models of hypertension. The cardiac tissue ANP contents were not significantly changed, but the tissue ANP mRNA levels were upregulated in the hypertrophied heart in these two models of hypertension. It is suggested that the cardiac ANP system is transcriptionally enhanced by cardiac hypertrophy associated with hypertension, independent of the systemic RAS.

Atrial natriuretic factor in two kidney - two clip renovascular hypertension in the rat

Hig levels of circulating atrial natriuretic factor (ANF) have been reported in several physiopathologic conditions like hypertension, heart and renal failure, pregnancy and high sodium intake. Nevertheless, neither relationships with water-sodium space regulation nor the role of an ANF vascular relaxant effect have been yet defined. The aim of present experiments was to characterize the contribution of circulating ANF and its vascular relaxing effects in the two kidney-two clip (2K2C) experimental model of renovascular hypertension. Complementary, plasma metabolites nitrite/nitrate of nitric oxide (NO) was examined because of mediation for both (NO an ANF) through cGMP. The results showed (two-four weeks after surgery): indirect sistolic blood pressure (mmHg), 186 + 4 in HT and 122 + 1 in SH (p<0.001); a significant increase of plasma ANF (fmol/ml) in HT (n = 7, 1221 + 253) vs. SH (n = 9, 476 + 82; p < 0.02). Nitrate/nitrite plasma concentrations (mumol/l) were mpt different between SH and. The relaxant effect of ANF (10(-9), 10(-8) and 10(-7) M) on phenylephrine (3,5 x 10(-6) M) contracted rings from HT rats was smaller than SH rats (10(-8) M, p < 0.05). Contractions to phorbol 12, 13-dibutyrate (seven weeks after surgery) were significantly higher in rings from HT rats (p < 0.001). We conclude: 1) in addition to decreased granularity in atrial myocardiocytes, high circulating values of ANF here described suggest an increased turnover of the peptide in 2K2C hypertensive rats; 2) lower significant vascular relaxant effects in HT rats would indicate down regulation of ANF receptors in this model; the latter would derive from high plasma ANF concentration and, tentatively, because of greater activity of protein kinase C in the vascular wall; 39 similar values of plasma nitrite/nitrate in SH and HT rats would indicate a comparable NO circulating availability in both groups.

Neuroendocrine regulation of salt and water metabolism

Neurons which release atrial natriuretic peptide (ANPergic neurons) have their cell bodies in the paraventricular nucleus and in a region extending rostrally and ventrally to the anteroventral third ventricular (AV3V) region with axons which project to the median eminence and neural lobe of the pituitary gland. These neurons act to inhibit water and salt intake by blocking the action of angiotensin II. They also act, after their release into hypophyseal portal vessels, to inhibit stress-induced ACTH release, to augment prolactin release, and to inhibit the release of LHRH and growth hormone-releasing hormone. Stimulation of neurons in the AV3V region causes natriuresis and an increase in circulating ANP, whereas lesions in the AV3V region and caudally in the median eminence or neural lobe decrease resting ANP release and the response to blood volume expansion. The ANP neurons play a crucial role in blood volume expansion-induced release of ANP and natriuresis since this response can be blocked by intraventricular (3V) injection of antisera directed against the peptide. Blood volume expansion activates baroreceptor input via the carotid, aortic and renal baroreceptors, which provides stimulation of noradrenergic neurons in the locus coeruleus and possibly also serotonergic neurons in the raphe nuclei. These project to the hypotlalamus to activate cholinergic neurons which then stimulate the ANPergic neurons. The ANP neurons stimulate the oxytocinergic neurons in the paraventricular and supraoptic nuclei to release oxytocin from the neural lobe which circulates to the atria to stimulate the release of ANP. ANP causes a rapid reduction in effective circulating blood volume by releasing cyclic GMP which dilates peripheral vessels and also acts within the heart slow its rate and atrial force of contraction. The released ANP circulates to the kidney where it acts through cyclic GMP to produce natriuresis and a return to normal blood volume.