RESUMEN
The hypotensive, natriuretic, and diuretic actions of human atrial natriuretic factor-(99-126) (hANF) are accompanied by an elevation of cyclic guanosine monophosphate (cGMP) in plasma and urine. However, the oxidized hANF analogue, human [Met-O110]ANF-(99-126) (Met-O-ANF), has been reported to be unable to increase cGMP (Biochem. Biophys. Res. Commun. 128: 538-546). We employed this oxidized peptide to evaluate the relationship between its biological effects and cGMP generation, with cGMP serving as a marker of the recognized property of ANF to stimulate particulate guanylate cyclase. Met-O-ANF appeared to be a partial agonist, exhibiting a decreasing order of relative potency of hypotensive, vasorelaxant, diuretic, and natriuretic functions compared to hANF. A lower degree of cGMP increases was achieved by this analogue in cultured smooth muscle and endothelial cells. Met-O-ANF doses, which led to a significant increase in diuresis, were neither natriuretic nor accompanied by an increase of urinary cGMP. We were thus able to dissociate the diuretic and natriuretic effects of ANF. High doses of the oxidized analogue were required to elevate cGMP levels in plasma and urine. In isolated kidney fractions, Met-O-ANF's action on cGMP was significantly lower in glomeruli (fivefold less), virtually absent in the collecting duct, yet only slightly different (20% less) in thick ascending limb. Our results indicate that the diuretic and natriuretic effects are exerted at distinct sites, with only the natriuresis being related to an increase of extracellular cGMP. The variability of differential potency of biological and biochemical effects from tissue to tissue of these two forms of human ANF support the notion of the heterogeneity of the ANF effector system.
Asunto(s)
Factor Natriurético Atrial/fisiología , Diuresis , Natriuresis , Animales , GMP Cíclico/sangre , GMP Cíclico/orina , Riñón/efectos de los fármacos , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Ratas , Ratas Endogámicas , Vasodilatación/efectos de los fármacosRESUMEN
Atrial natriuretic peptide (ANP) specifically stimulates particulate guanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been recognized as its second messenger. Spontaneously hypertensive rats (SHR) have elevated plasma ANP levels, but manifest an exaggerated natriuretic and diuretic response to exogenous ANP when compared to normotensive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normotensive strains (Wistar 13 +/- 2; Wistar-Kyoto 12 +/- 2; Sprague-Dawley 14 +/- 2) while a maximal 33 +/- 3-fold elevation occurs in SHR (P < 0.001). This hyperresponsiveness of cGMP is reproducible in intact glomeruli from SHR from various commercial sources. Furthermore, this abnormality develops early in life, even before hypertension is clearly established, and persists despite pharmacological modulation of blood pressure, indicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in membranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor subtypes between normotensive and hypertensive strains, as assessed by competitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate guanylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactivation analysis does not evoke a disturbance in the size of regulatory elements normally repressing enzymatic activity, while the expression of particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PCR) transcript titration assay, manifests a selective increase of one guanylate cyclase subtype. Our data suggest that in hypertension, genetic overexpression of the ANP A-receptor subtype is related to the exaggerated biological response to ANP in this disease.
Asunto(s)
Factor Natriurético Atrial/metabolismo , GMP Cíclico/biosíntesis , Regulación de la Expresión Génica , Hipertensión/metabolismo , ARN Mensajero/biosíntesis , Ratas Endogámicas/metabolismo , Receptores del Factor Natriurético Atrial/biosíntesis , Marcadores de Afinidad , Animales , Secuencia de Bases , Relación Dosis-Respuesta a Droga , Guanilato Ciclasa/metabolismo , Glomérulos Renales/metabolismo , Masculino , Datos de Secuencia Molecular , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores del Factor Natriurético Atrial/clasificación , Receptores del Factor Natriurético Atrial/genéticaRESUMEN
Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.
Asunto(s)
Cardiomegalia/genética , Miocardio/metabolismo , Receptores de Angiotensina/genética , Angiotensina II/farmacología , Animales , Animales Modificados Genéticamente , Animales Recién Nacidos , Unión Competitiva , Presión Sanguínea/efectos de los fármacos , Calcio/metabolismo , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Membranas/metabolismo , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Perfusión , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Factores de Tiempo , Transgenes/genéticaRESUMEN
OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.
Asunto(s)
Angiotensina II/sangre , Factor Natriurético Atrial/sangre , Insuficiencia Cardíaca/fisiopatología , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Factor Natriurético Atrial/biosíntesis , Volumen Sanguíneo , GMP Cíclico/sangre , GMP Cíclico/orina , Diuresis , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/orina , Masculino , Miocardio/metabolismo , Ramipril/análogos & derivados , Ramipril/farmacología , Ratas , Ratas Wistar , Estadísticas no Paramétricas , Tetrazoles/farmacología , Valina/análogos & derivados , Valina/farmacología , ValsartánRESUMEN
In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523 +/- 54 to 1258 +/- 330 pmol/L, P<.05) and controls (184 +/- 28 to 514 +/- 107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789 +/- 154 to 2674 +/- 577 microL/80 min and 99 +/- 31 to 352 +/- 96 micromol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure-induced cardiac hypertrophy independent of hemodynamic effects.
Asunto(s)
Alanina/análogos & derivados , Factor Natriurético Atrial/sangre , Diuresis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/metabolismo , Neprilisina/antagonistas & inhibidores , Alanina/farmacología , Angiotensina II/sangre , Animales , Aorta Abdominal/cirugía , Derivación Arteriovenosa Quirúrgica , GMP Cíclico/orina , Hemodinámica/efectos de los fármacos , Masculino , Natriuresis/efectos de los fármacos , Neprilisina/fisiología , Ratas , Ratas Wistar , Renina/sangre , Vena Cava Inferior/cirugíaRESUMEN
BACKGROUND: This study evaluated the short-term and long-term effects of the angiotensin II type 1 receptor antagonist candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure (CHF). METHODS: In this multicenter, double-blind, parallel-group study, 218 patients with CHF (New York Heart Association class II or III) with impaired left ventricular function (ejection fraction < or =40%) and pulmonary capillary wedge pressure > or =13 mm Hg were randomly assigned to 12 weeks of treatment with placebo (n = 44) or candesartan cilexetil (2 mg [n = 45], 4 mg [n = 46], 8 mg [n = 39], or 16 mg [n = 44]) once daily after a 2-week placebo run-in period. Hemodynamic measurements were performed by right heart catheterization over a 24-hour period after single (day 1) and repeated (3-month) treatment with the study drug. RESULTS: On regression analysis of the time-response curves, single and multiple doses of candesartan cilexetil produced sustained, significant, and dose-dependent reductions in pulmonary capillary wedge pressure (short-term effect P =.036, long-term effect P =.035) and mean pulmonary arterial pressure (short-term effect P =.031, long-term effect P =.042). Systemic vascular resistance showed a trend toward decreasing with dose on short-term and long-term treatments. No consistent changes were seen in cardiac index. Compensatory increases in plasma renin activity and angiotensin II levels with decreases in aldosterone and atrial natriuretic peptide were dose-dependent and significant. Candesartan cilexetil improved clinical symptoms, stabilized patient New York Heart Association status compared with placebo, and was judged to be an efficacious treatment by the investigators. More patients receiving placebo stopped the trial prematurely because of an adverse event than in any candesartan cilexetil group, and there was no excess of deaths in any treatment group. Candesartan was safe and well tolerated at all dosages. CONCLUSIONS: Candesartan cilexetil demonstrated significant short-term and long-term improvements in hemodynamic, neurohormonal, and symptomatic status and was well tolerated in patients with CHF.
Asunto(s)
Bencimidazoles/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Hormonas/sangre , Tetrazoles , Adolescente , Adulto , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Antagonistas de Receptores de Angiotensina , Factor Natriurético Atrial/sangre , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Placebos , Profármacos/farmacología , Profármacos/uso terapéutico , Análisis de Regresión , Renina/sangre , Resultado del TratamientoRESUMEN
METHODS: Atrial natriuretic peptide (ANP) was labeled in high specific activity using 123I (p,2n). The biodistribution of 123I-ANP was studied in green vervet monkeys by gamma scintigraphy and in rats by dissection and gamma counting. Iodine-125-ANP was also studied in monkeys by in vitro autoradiography. RESULTS: Iodine-123-ANP showed rapid blood clearance with localization to ANP receptors in the kidneys and lungs, which accounted for 35% of total uptake. In vivo competition imaging studies using cold ANP99-126 and C-ANP102-121 proved that uptake is receptor mediated and allowed imaging of the differential biodistribution of A/B and C-ANP receptor families. Thus, it was possible through the use of selective receptor occupation to prevent uptake in certain organs and to effectively steer the labeled ANP to others. The observed biodistribution patterns were confirmed by an in vitro study using 125I-ANP in the same monkeys, which correlated the scintigraphic images with receptor distribution. An in vivo biodistribution study in rats showed a profound effect of specific activity on biodistribution, with a cutoff for receptor uptake at less than 3000 Ci/mmole. CONCLUSION: Gamma scintigraphy with 123I-ANP permits the imaging of ANP receptors in vivo. In contrast to receptor imaging with either organic molecules or antibodies, ANP provides rapid first-pass uptake and substantial accumulation (%dose/organ approximately 20% or greater) in receptors. The key to receptor imaging with peptides is high specific activity. Labeled ANP offers potential as a diagnostic tool for diabetic nephropathy, particularly for quantifying the involvement of glomerular disease.
Asunto(s)
Factor Natriurético Atrial , Radioisótopos de Yodo , Receptores del Factor Natriurético Atrial/análisis , Animales , Autorradiografía , Unión Competitiva , Chlorocebus aethiops , Semivida , Corazón/diagnóstico por imagen , Riñón/diagnóstico por imagen , Riñón/metabolismo , Hígado/diagnóstico por imagen , Hígado/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Masculino , Miocardio/metabolismo , Fragmentos de Péptidos , Cintigrafía , Ratas , Ratas Sprague-DawleyRESUMEN
The term ventricular remodeling has been coined to describe the geometrical changes in size and shape of the left ventricle occurring after large myocardial infarcts. We do not exactly know what initiates this process. Slipping of myofilaments following destruction of connective tissue--probably due to metalloproteinase activation--could be the initial event. As a consequence, wall stress is increased triggering deleterious adaptation processes, such as: - intracardiac angiotensin II generation; - cardiac endothelin formation and release; - pro-apoptotic signals for cardiomyocytes; - hypertrophic signals for fibroblasts and cardiomyocytes. This cascade of events is not only observed in the process of remodeling following myocardial infarction but is also operating during the progression of heart failure. Therapeutic principles therefore are similar in both conditions: - reduction of wall stress (pharmacological or mechanical unloading of the heart); - blockade of angiotensin II generation or of AT1-receptors (ACE-inhibitors or AT1 antagonists); - blockade of endothelin receptors (ET(A)-blockers); - blockade of adrenergic receptors (preferably beta1-adrenergic receptor blockers). Better understanding of the molecular mechanisms of the remodeling process already has fueled the search for new therapeutic interventions (such as endothelin receptor blockers, aldosterone antagonists and growth hormone application). Continuous research in this field may be especially rewarding if we will succeed in identifying the very first step in the cascade.
Asunto(s)
Infarto del Miocardio/fisiopatología , Remodelación Ventricular , Animales , Humanos , Infarto del Miocardio/patologíaRESUMEN
OBJECTIVE: Recently, deletion of specific genes by so called knock-out techniques has become important for investigating the pathogenesis of various diseases. This form of genetic engineering is widely performed in murine models. There are, however, only a limited number of mouse models available in cardiovascular pathology. The objective of this study, therefore, was to develop a new model of overt congestive heart failure associated with myocardial hypertrophy in the mouse. METHODS: Female C57/BL6 mice weighing 19-20 g were anesthetized with ether. After abdominal incision, the aorta was temporarily clamped proximal to the renal arteries. The aorta was then punctured with a needle (outer diameter 0.6 mm) and the needle was further advanced into the adjacent vena cava. After withdrawal of the needle, the aortic puncture site was sealed with cyanoacrylate glue. The clamp was removed, and the patency of the shunt was visually verified as swelling and mixing of venous and arterial blood in the vena cava. Sham-operated mice served as controls. RESULTS: Perioperative mortality of mice with aortocaval shunt was 42%. Four weeks after shunt induction, mice showed a significant cardiac hypertrophy with a relative heart weight of 7.5+/-0.2 mg/100 g body weight (vs. 5.1+/-0.7 mg/100 g in control mice, P<0.001). While no changes in blood pressure and heart rate occurred, left ventricular enddiastolic pressure was significantly increased in mice with shunt, and left ventricular contractility was impaired from 6331+/-412 to 4170+/-296 mmHg/s (P<0.05). Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cGMP as humoral markers of heart failure as well as ventricular expression of ANP- and brain natriuretic peptide (BNP)-mRNA were significantly increased in mice with shunt compared to control mice. CONCLUSIONS: The aortocaval shunt in the mouse constitutes a new model of overt congestive heart failure with impaired hemodynamic parameters and may be a useful tool to investigate the role of particular genes in the development of heart failure.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Animales , Derivación Arteriovenosa Quirúrgica , Factor Natriurético Atrial/sangre , Factor Natriurético Atrial/metabolismo , Presión Sanguínea/fisiología , Volumen Cardíaco/fisiología , Cardiomegalia/etiología , Cardiomegalia/fisiopatología , Femenino , Insuficiencia Cardíaca/etiología , Frecuencia Cardíaca/fisiología , Ratones , Ratones Endogámicos C57BL , Péptido Natriurético Encefálico/metabolismoRESUMEN
We have successfully visualized atrial natriuretic peptide (ANP) receptors in vivo using nuclear imaging. 123I-Labelled ANP, injected in green vervet monkeys, was rapidly bound to ANP receptors in the kidneys and lungs. That the observed uptake was receptor mediated was demonstrated with competition studies using simultaneous injection of unlabelled ANP 99-126. It was possible to distinguish between the ANP receptor subtypes by the use of selective antagonists. Thus coinjection of ANP 102-121-des[Gln, Ser, Gly, Leu, Gly] (C-ANP), an ANP analog that selectively binds to the ANP C-receptor, decreased uptake in the kidneys by 50% but increased relative uptake in the lungs and soft tissues. This method permits for the first time, the dynamic in vivo analysis of ANP receptors and their interaction with endogenous ligand. Differences and changes in local ANP receptor concentrations and occupancy could be detected. Since ANP receptor density and affinity are influenced by various physiological and pathological conditions, clinical and diagnostic applications seem possible.
Asunto(s)
Receptores del Factor Natriurético Atrial/metabolismo , Animales , Factor Natriurético Atrial/farmacocinética , Chlorocebus aethiops , Cámaras gamma , Radioisótopos de Yodo , Riñón/metabolismo , Pulmón/metabolismo , MasculinoRESUMEN
Neutral endopeptidase inhibition (NEPI) provides a potential avenue to modulate the actions of atrial natriuretic peptide (ANP). We tested the hypothesis that acute and chronic NEPI increased the renal responses at baseline and after acute volume expansion in rats. ANP plasma levels and cGMP excretion were significantly increased with acute NEPI by SQ 28.603, whereas chronic inhibition with SCH 34826 did not lead to any changes. The ratio of cGMP excretion per plasma ANP, however, was significantly increased (6.2 +/- 0.9) by chronic treatment with SCH 34826 compared to chronic vehicle treatment (4.2 +/- 0.7) indicating an activated renal ANP receptor system. Baseline diuresis and natriuresis were enhanced with acute but not with chronic treatment. After acute volume expansion, ANP increased five-fold with acute NEPI, whereas it only increased about 70% in chronically inhibited rats. The natriuretic (497 +/- 62 vs. 329 +/- 42 micromol/60 min with vehicle, P < 0.05) and diuretic responses were significantly enhanced with chronic treatment. Together with an increased cGMP/ANP ratio, these data suggest that chronic activation of the renal ANP system after long-term NEPI facilitated the excretion of an acute volume load. These findings may have therapeutic implications in patients with chronic sodium retention.
Asunto(s)
Factor Natriurético Atrial/sangre , GMP Cíclico/sangre , Natriuresis , Neprilisina/antagonistas & inhibidores , Alanina/análogos & derivados , Alanina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diuresis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
Heart failure is characterized by increased vascular resistance and water retention. Adrenomedullin is a peptide hormone with vasodilating and diuretic properties whose efficacy in heart failure has not been well established. We used an aortocaval shunt model of moderate heart failure in rats and infused increasing doses of adrenomedullin, both as bolus injections and 20-min infusions. In controls, a clear dose-dependent 4.8+/-1.0 to 13.6+/-2.3 mm Hg decrease in arterial blood pressure was observed after injection of 1 microg to 30 microg of adrenomedullin. In rats with aortocaval shunt, the hypotensive responses were significantly diminished. The urine flow rate, which was diminished at baseline in rats with aortocaval shunt, was increased and normalized by adrenomedullin administration. The glomerular filtration rate increased after infusion of adrenomedullin (0.5 microg/kg min(-1)) from 2.37+/-0.25 to 3.47+/-0.43 ml/min (P<0.01) in controls and from 1.79+/-0.33 to 2.58+/-0.49 (P<0.05) in rats with aortocaval shunt. Similarly, renal blood flow was significantly increased by adrenomedullin in both groups. Our results indicate a beneficial effect of adrenomedullin on renal function in rats with aortocaval shunt. These data suggest that adrenomedullin might be of potential therapeutic value in heart failure, without inordinately decreasing blood pressure.
Asunto(s)
Cardiotónicos/farmacología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , Péptidos/farmacología , Adrenomedulina , Animales , Derivación Arteriovenosa Quirúrgica , AMP Cíclico/orina , GMP Cíclico/orina , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Masculino , Natriuresis/efectos de los fármacos , Péptidos/administración & dosificación , Ratas , Ratas Wistar , Circulación Renal/efectos de los fármacosRESUMEN
The pyrimidine precursor orotic acid (OA) is a constituent of dairy products and therapeutic drugs. Several recent publications point towards a tumor promoting activity of OA in rat liver. An increased production of reactive oxygen has been discussed as a possible mechanism, leading to lipid peroxidation and DNA single strand breaks. In view of contradictory results, this postulated prooxidative action of OA was reexamined with new experimental techniques. Weanling Sprague-Dawley rats were fed 1% OA in different diets for 4-35 days. The NADPH-mediated lipid peroxidation in liver homogenate and microsomes was determined in vitro by analysis of low-level chemiluminescence (CL) and the strongly correlated formation of malondialdehyde (MDA). In no case did treatment with OA result in an increase of lipid peroxidation in vitro nor did such treatment enhance the generation of reactive oxygen as measured by lucigenin CL. In accordance, the total cytochrome P-450 content as well as the activity of individual P-450 isoenzymes were unchanged. Treatment with OA did not elevate the MDA content of fresh liver homogenate when butylated hydroxytoluene (BHT) was present in the test system. However, when the antioxidant was omitted, increased levels of thiobarbituric acid reactive material were found which correlated with the triglyceride content. This could explain some published data that have been taken as indication for a prooxidative action of OA. Evidence against an increased lipid peroxidation in vivo is given by the analysis of ethane exhalation. Furthermore, no increase in DNA single strand breaks by OA treatment could be observed by the alkaline elution technique. These results do not support the hypothesis of a prooxidative activity of OA. The observed reversible decrease of the GSH/GSSG ratio is assumed to result from the reduced size of the phosphopyridine nucleotide pool due to purine deficiency and an increased consumption of NADPH by the enhanced reductive degradation of pyrimidines.
Asunto(s)
Peroxidación de Lípido/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Ácido Orótico/toxicidad , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Daño del ADN/efectos de los fármacos , ADN de Cadena Simple , Femenino , Glutatión/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Oxidación-Reducción , Ratas , Ratas EndogámicasRESUMEN
Adrenomedullin (AM) is a peptide hormone with vasodilating and natriuretic properties. AM plasma concentrations are elevated in heart failure. Whether cardiac AM-mRNA synthesis is increased in heart failure is not known. We measured AM-mRNA/GAPDH-mRNA in all four heart chambers in compensated and overt heart failure in rats with two different sizes of aortocaval shunt. Left and right atrial AM-mRNA expressions were unchanged in both heart failure models. Similarly, left and right ventricular AM-mRNA expressions were unchanged in compensated heart failure. In overt heart failure, however, the AM-mRNA expression was significantly increased in the left ventricle (145+/-20 vs. 100+/-3% of control, p<0.05). The right ventricular AM-mRNA expression was significantly increased only in a subgroup of animals with pulmonary congestion (lung weight >2.0 g, 141+/-16 vs. 100+/-11% of control, p<0.05). Ventricular AM concentrations were elevated in both ventricles in overt heart failure. AM plasma concentrations were significantly higher in the subgroup with pulmonary congestion than in rats with compensated heart failure (496+/-95 vs. 143+/-7 pmol/l, p<0.01). These data indicate that ventricular AM-mRNA expression and AM concentrations were upregulated only in advanced stages of heart failure. However, the exact contribution of cardiac AM synthesis to the increased AM plasma levels remains to be established.
Asunto(s)
Insuficiencia Cardíaca/metabolismo , Miocardio/metabolismo , Péptidos/metabolismo , ARN Mensajero/biosíntesis , Adrenomedulina , Animales , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Atrios Cardíacos/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/metabolismo , Hemodinámica , Pulmón/patología , Masculino , Miocardio/patología , Tamaño de los Órganos , Péptidos/sangre , ARN Mensajero/análisis , Ratas , Ratas WistarRESUMEN
Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas de Hormonas/uso terapéutico , Neurotransmisores/antagonistas & inhibidores , Aldosterona/fisiología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bencimidazoles/uso terapéutico , Compuestos de Bifenilo , Insuficiencia Cardíaca/fisiopatología , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Neurotransmisores/fisiología , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina/fisiología , Tetrazoles/uso terapéuticoRESUMEN
This review article summarizes the long-term standard therapy for patients with myocardial infarction. The chronic therapy is able to significantly improve quality of life and survival of affected patients. Previous studies showed that in most western countries, the established standard therapy is not given to all patients who would benefit from chronic treatment. The essential parts of today's myocardial infarction treatment consists of effective beta-blockade, inhibition of the angiotensin-conversion enzyme, inhibition of platelet aggregation and lipid lowering agents. This article reviews the clinical benefits which may be expected from each of these therapeutic approaches. Newer, but not yet proven strategies, like blockade of the angiotensin receptor subtype 1 and treatment with antioxidative agents will be discussed.
Asunto(s)
Fármacos Cardiovasculares/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Aspirina/efectos adversos , Aspirina/uso terapéutico , Fármacos Cardiovasculares/efectos adversos , Humanos , Infarto del Miocardio/mortalidad , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de SupervivenciaRESUMEN
Natriuretic peptides are important regulators of vascular resistance and volume and electrolyte homeostasis. The quantification of natriuretic peptide receptor (NPR) mRNA is important for the understanding of the regulation of this humoral system, but is difficult due to low expression of the NPR mRNA. We report here on the evaluation of a polymerase chain reaction (PCR)-aided transcript titration assay for quantification of all three NPR subtypes (NPR-A, NPR-B, and NPR-C) mRNA. A multispecific internal standard RNA with parts of NPR-A, NPR-B, NPR-C and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nucleotide sequences was constructed and reverse transcription of standard and sample RNA (400 ng) was performed in parallel for all three NPRs and GAPDH. The specific PCR yielded differently sized products, which were quantified by high performance liquid chromatography (HPLC). The determination of specific mRNA concentrations was not influenced by cDNA input and did not depend on the PCR cycle number. Linearity between sample RNA input and mRNA concentration was demonstrated. Application of the evaluated method showed that the NPR-A mRNA expression was the most abundant of the three natriuretic peptide receptor mRNAs in rat lungs, glomeruli and left ventricles, followed by the NPR-C mRNA and the NPR-B mRNA expression. Thus, the described method allows the reliable quantification of the specific mRNA expression of all three NPRs with small amounts of RNA. The presented method might foster future research on the regulation of this humoral system in cardiovascular and kidney diseases.
Asunto(s)
ARN Mensajero/metabolismo , Receptores del Factor Natriurético Atrial/genética , Animales , Secuencia de Bases , Cromatografía Líquida de Alta Presión , ADN Complementario , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Masculino , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Effects of angiotensin-converting enzyme inhibition (ACEI) on autonomic responses and hemodynamics in patients with congestive heart failure (CHF) subjected to isometric exercise have not been studied. We tested whether acute ACEI might influence the effects of isometric exercise in patients with CHF. In the first part of the study we showed that isometric exercise increased blood pressure in the control group and in the CHF group, whereas cardiac output increased only in the control group. Stroke volume remained unchanged in the control group, whereas it decreased significantly in CHF group. We next analyzed the effect of acute ACEI (5 mg ramipril) on the decrease in cardiac output during isometric stress in patients with CHF. During isometric exercise mean blood pressure and heart rate increased similarly in both groups. However, cardiac output decreased during placebo by -0.48 +/- 0.12 L/min (p < 0.01) but not during ACEI. Spectral analysis of blood pressure showed an increase (p < 0.01) in the high-frequency parasympathetic component from 7.3% +/- 3.6% to 18.1% +/- 9.5% after ACEI. norepinephrine plasma levels increased after isometric stress in the placebo group, whereas other hormones did not change. ACEI prevented the norepinephrine increase after isometric stress. Thus the decrease in cardiac output during isometric exercise in patients with CHF was prevented by acute ACEI. The effect of ACE inhibition may be related to reduced sympathetic activity.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Ejercicio Físico , Insuficiencia Cardíaca/fisiopatología , Ramipril/uso terapéutico , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Sistema Nervioso Autónomo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Ecocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Ramipril/farmacología , Volumen Sistólico/efectos de los fármacosRESUMEN
UNLABELLED: The increase of sympathetic activity in heart failure is accompanied by a reduced parasympathetic tone. The renin-angiotensin system has not only multiple interactions with the sympathetic nervous system, but may also influence vagal tone directly by angiotensin II. Animal studies show a reduction of parasympathetic tone by a direct action of angiotensin II in the area postrema where the blood brain barrier is absent. It is possible that, in addition to the sympathetic and renin-angiotensin system, the parasympathetic nervous system may also influence prognosis in heart failure. Therefore, baroreflex sensitivity as (CBS) an index of vagal tone was examined in 35 patients with moderate to severe heart failure (NYHA II-III). Independent of the severity of heart failure BS was the lower the higher plasma-renin-activity was. Fifty-six months after the initial examination a comparison of the surviving patients (Group 1, n = 20) with the patients who died or underwent heart transplantation (Group 2, n = 15) did not reveal significant differences in the initial hemodynamic data. However, group 2 patients showed a tendency to higher initial plasma-renin-activity and significantly lower BS 1.3 +/- 0.2 vs. 2.2 +/- 0.3 ms/mm Hg; p < 0.05). CONCLUSION: In patients with heart failure a relation between the renin-angiotensin system and the parasympathetic nervous system is likely as there is a significant negative relationship between BS and plasma-renin-activity. Among patients with a similar degree of heart failure a low vagal tone identifies patients with a poor prognosis.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Sistema Nervioso Parasimpático/fisiopatología , Sistema Renina-Angiotensina/fisiología , Adulto , Anciano , Cardiomiopatía Dilatada/fisiopatología , Enfermedad Coronaria/fisiopatología , Femenino , Estudios de Seguimiento , Hemodinámica/fisiología , Humanos , Masculino , Persona de Mediana Edad , Presorreceptores/fisiopatología , Nervio Vago/fisiopatologíaRESUMEN
BACKGROUND: The discovery of new properties of angiotensin converting enzyme (ACE) inhibitors in addition to their well-known ability to lower blood-pressure, such as antiproliferative actions and antiadrenergic and vagal-stimulating effects, has contributed to the usefulness of this class of agents in the prevention and treatment of cardiovascular diseases. METHODS AND RESULTS: The contribution of an activated endocrine and/or cardiac paracrine renin-angiotensin system to the progression of cardiovascular diseases with the exception of renovascular hypertension is not fully understood. In particular, the following questions were addressed: 1) Is the facilitation of noradrenaline release in the genesis of arrhythmias a target for ACE inhibition? 2) Is an impaired nutritional cardiac blood flow in heart failure a target for ACE inhibition? 3) Is the intimal hyperplasia that results from coronary angioplasty a target for ACE inhibition? 4) Is the diastolic dysfunction associated with left ventricular hypertrophy in essential hypertension a target for ACE inhibition? In an isolated rat heart preparation with ischemia-induced arrhythmias, none of the ACE inhibitors nor an angiotensin II antagonist was able to significantly suppress the incidence or severity of arrhythmias. In 12 patients with New York Heart Association functional class II-IV heart failure, a fall in cardiac filing pressures after ACE inhibition was associated with an immediate rise in cardiac output and an increase in coronary blood flow of almost 30%. In 24 patients with angina at rest, a preceding percutaneous transluminal coronary angioplasty, and a second angioplasty, control angiograms at 6 months revealed a high degree of restenosis in both ACE inhibitor-treated and placebo patients. Luminal narrowing amounted to 72% in the placebo group and 61% in the ACE inhibitor group. The differences between placebo and enalapril were statistically not significant. In 12 patients with essential hypertension treated with 5 mg cilazapril, left ventricular mass was reduced by 30%, which was closely related to the change in mean arterial blood pressure. The concomitant normalization of the diastolic filling pattern by ACE inhibition, however, was not related to the respective changes in blood pressure. CONCLUSIONS: Promising experimental data regarding the antiproliferative effects of ACE inhibitors in preventing restenosis could not be transferred into clinical benefits for patients who underwent repeat coronary angioplasty. Possible antiarrhythmic effects of ACE inhibitors are not likely to be caused by their suppression of noradrenaline release during myocardial ischemia. ACE inhibition was effective in reducing coronary resistance in patients with severe heart failure, thereby augmenting nutritional cardiac blood flow. ACE inhibition also effectively induced a regression of left ventricular hypertrophy in essential hypertension. The associated normalization of diastolic filling pattern may represent an important goal in the treatment of hypertension.