RESUMEN
Gap-junctions are specialized regions of intercellular contacts allowing electrical impulse propagation among adjacent cardiomyocytes. Connexin43 (Cx43) is the predominant gap-junction protein in the working ventricular myocardium and its reduced expression has been extensively implicated in the genesis of conduction abnormalities and re-entry arrhythmia of chronically hypertrophied hearts. In contrast, data on the role played by this protein during cardiac remodeling and early phases of developing hypertrophy are lacking. Therefore, in the present study, we investigated this issue using an experimental model of pig left ventricle (LV) volume overloading consisting in the creation of an aorto-cava fistula. At scheduled times (6, 24, 48, 96, 168 h, and 2, 3 months after surgery) echocardiographic and haemodynamic measurements were performed and myocardial biopsies were taken for the morphological and biochemical analyses. When faced with the increased load, pig myocardium underwent an initial period (from 6 up to 48 h) of remarkable tissue remodeling consisting in the occurrence of cardiomyocyte damage and apoptosis. After that time, the tissue developed a hypertrophic response that was associated with early dynamic changes (up-regulation) in Cx43 protein expression, as demonstrated by Western blot and confocal immunofluorescence analyses. However, an initial transient increase of this protein was also found after 6 h from surgery. With the progression of LV hypertrophy (from 168 hr up to 3 months), a reduction in the myocardial Cx43 expression was, instead, observed. The increased expression of Cx43 protein during acute hypertrophic response was associated with a corresponding increase in the levels of its specific mRNA, as detected by RT-PCR. We concluded that up-regulation of Cx43 gap-junction protein could represent an immediate compensatory response to support the new working conditions in the early stages of ventricular overloading.
Asunto(s)
Adaptación Fisiológica/fisiología , Conexina 43/biosíntesis , Corazón/fisiología , Miocardio/metabolismo , Animales , Apoptosis/fisiología , Western Blotting , Tamaño de la Célula , Densitometría , Fibrosis , Hemodinámica/fisiología , Microscopía Confocal , Microscopía Electrónica , Contracción Miocárdica/fisiología , Miocardio/ultraestructura , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Porcinos , Función Ventricular Izquierda/fisiologíaRESUMEN
Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [(3)H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (P<0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (P<0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (P<0.01), whereas cardiac [(3)H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise.
Asunto(s)
Ejercicio Físico/fisiología , Corazón/inervación , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Sistema Nervioso Simpático/fisiopatología , Adulto , Angiotensina II/biosíntesis , Ecocardiografía , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Miocardio/metabolismo , Norepinefrina/sangre , FútbolRESUMEN
OBJECTIVES: The aim of this study was to investigate the activity of the cardiac renin-angiotensin system (RAS) in unstable angina (UA). BACKGROUND: Angiotensin (Ang) II locally produced by continuously operating cardiac RAS may affect the pathophysiology of UA. METHODS: In 35 patients with UA, 32 with stable effort angina (SA) and 21 with atypical chest pain (controls), cardiac RAS was investigated during coronary angiography after five days of Holter monitoring by combining the measurement of aorta-coronary sinus gradient for Ang I and Ang II with the kinetics study of 125I-Ang I. Messenger RNAs (mRNA) for all the components of RAS were also quantified with the reverse transcriptase-polymerase chain reaction (RT-PCR) and localized by in situ hybridization in myocardial biopsy specimens from patients who underwent aorta-coronary bypass surgery. RESULTS: Cardiac Ang II generation was higher in patients with UA than it was in patients with SA or in controls (p < 0.001) due to increased de novo cardiac Ang I formation and its enhanced fractional conversion rate to Ang II. Messenger RNA levels for angiotensinogen (AGTN), angiotensin-converting enzyme (ACE) and Ang II type 1 (AT1) subtype receptors were higher in patients with UA (p < 0.01) than they were in patients with SA or in control hearts. Messenger RNAs for AGTN and ACE were almost exclusively expressed on endothelial and interstitial cells. Angiotensin II formation was correlated with ischemia burden (p < 0.001). However, the amount of Ang II formed and the expression levels of mRNAs for AGTN, ACE and AT1 were not related to the time that had elapsed since the last anginal attack. CONCLUSIONS: In patients with UA, cardiac RAS is activated, resulting in increased Ang II formation. Myocardial ischemia is essential for RAS activation, but it is unlikely to be a direct and immediate cause of RAS activation.
Asunto(s)
Angina Inestable/fisiopatología , Sistema Renina-Angiotensina , Anciano , Angiotensina II/fisiología , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Miocardio/enzimología , ARN Mensajero/análisis , Receptores de Angiotensina/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Animal experiments have shown an increase in prepro-endothelin-1 (prepro-ET-1) mRNA expression in the clipped kidney but none in the aortic and mesenteric arteries in 2-kidney, 1-clip Goldblatt hypertensive rats. The present study was aimed at investigating whether plasma and renal endothelin-1 (ET-1) systems are differently activated in patients with renovascular hypertension (RH). The plasma concentration and urinary excretion of ET-1 were measured in 5 patients with RH (before and after successful renal angioplasty), in 7 patients with essential hypertension (EH), and in 8 normotensive control subjects. Immediately before renal angioplasty, plasma samples for ET-1 and plasma renin activity (PRA) measurements were withdrawn from the aorta and both renal veins. Unlike the PRA, the plasma ET-1 concentration did not significantly differ between the involved and the uninvolved sides. The urinary ET-1 excretion level (Fig 1) was markedly increased in patients with RH (30+/-4 ng/g urinary creatinine (UC) vs. 2.5+/-0.2 ng/g UC and 2.6+/-0.5 ng/g UC in control subjects and patients with EH, respectively; P<.001), whereas the plasma ET-1 concentration was normal (0.8+/-0.2 pg/mL vs. 0.65+/-0.3 pg/mL and 0.8+/-0.2 pg/mL in control subjects and EH, respectively, not significant). Renal angioplasty was followed in all patients by normalization of blood pressure and PRA. One week after angioplasty, urinary ET-1 decreased to one fourth of baseline (8.04+/-5.23 ng/g UC, P<.001 vs. values before angioplasty and P<.04 vs. control subjects) and normalized 1 month thereafter (3.13+/-1.62 ng/g UC, not significant vs. control subjects), whereas plasma ET-1 remained steady. The present findings clearly indicate that in patients with RH, urinary ET-1 excretion is increased, whereas plasma ET-1 concentration remains normal. Successful percutaneous transluminal renal angioplasty induced a notable reduction in ET-1 urinary excretion, whereas it did not affect ET-1 plasma concentration.
Asunto(s)
Endotelina-1/sangre , Endotelina-1/orina , Hipertensión Renal/sangre , Hipertensión Renal/orina , Anciano , Aldosterona/sangre , Angioplastia , Arteriosclerosis/cirugía , Presión Sanguínea , Ecocardiografía , Femenino , Humanos , Hipertensión Renal/cirugía , Masculino , Persona de Mediana Edad , Función Ventricular IzquierdaRESUMEN
On cardiac membranes and isolated cardiomyocytes from the human heart, cell-type distribution and functional activities of endothelin-1 (ET-1) receptor subtypes were investigated by using binding methods and messenger RNA (mRNA) in situ hybridization. The ET-receptor antagonist BMS-182874 selectively and competitively inhibits ET(A) receptors both on isolated myocytes and ventricular membranes with approximately 1,300 times greater affinity for ET(A) than ET(B) subtypes. The [125I]-ET-1 specific binding revealed 42.851+/-2,546 receptors/myocyte with a prevalent proportion of ET(A)-receptor subtypes on both myocytes (84+/-2%) and ventricular membranes (66+/-3%). In situ hybridization studies revealed that mRNA for ET(A) receptors was expressed on both myocytes and nonmyocyte cells, whereas mRNA for ET(B) receptors was almost exclusively expressed on fibroblasts and endothelial cells. Specific binding of [125I]-ET-1 to both myocytes and ventricular membranes in the presence of specific ET(A) (BMS-182874) and ET(B) (BQ-788)-receptor antagonists showed a displacement of [125I]-ET-1 by unlabeled ET-1, which were significantly faster from ET(B) than from ET(A). This suggests a clearance function of ventricular ET(B) receptors.
Asunto(s)
Miocardio/metabolismo , Receptores de Endotelina/metabolismo , Antihipertensivos/farmacología , Unión Competitiva , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Compuestos de Dansilo/farmacología , Antagonistas de los Receptores de Endotelina , Sustancias de Crecimiento/metabolismo , Humanos , Hibridación in Situ , Técnicas In Vitro , Cinética , Miocardio/citología , Receptor de Endotelina ARESUMEN
The present study aimed to investigate endothelin-1 (ET-1) receptors in human and swine cardiomyocytes with binding studies using ET(A) and ET(B) selective receptor antagonists (BMS-182874 and BQ-788, respectively). Cell distribution of mRNA expression for ET(A) and ET(B) subtypes was investigated by in situ hybridization using specific cDNA probes. The 1251-ET-1 binding, which reached equilibrium in about 120 min (Kobs = 0.051+/-0.003 min(-1)), was only partially displaceable by the addition of a large excess of ET-1 (about 15% with a half-life of 20 min). In equilibrium binding studies, 125I-ET-1 had a Kd of 0.43+/-0.08 nM and a maximum binding (Bmax) of 42.8+/-6.6 fmol/mg protein. ET(A) and ET(B) receptors are represented in human and swine cardiomyocytes with an 85:15 ratio as indicated by the biphasic pattern of competition of both BMS-182874 and BQ-788. In situ hybridization studies confirmed that myocytes mainly expressed mRNA for ET(A), whereas expression of mRNA for the ET(B) subtype was documented in non-myocyte cells. These results showed that ET-1 binds with high affinity and poor reversibility to specific receptors, in both human and swine isolated ventricular cardiomyocytes, without significant species differences.
Asunto(s)
Miocardio/metabolismo , Receptores de Endotelina/metabolismo , Adulto , Animales , Unión Competitiva , Antagonistas de los Receptores de Endotelina , Ventrículos Cardíacos/metabolismo , Humanos , Hibridación in Situ , Cinética , Persona de Mediana Edad , Receptor de Endotelina A , Receptor de Endotelina B , Porcinos , Función Ventricular IzquierdaAsunto(s)
Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Ensayos Clínicos como Asunto , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacología , Trombocitopenia/sangre , Trombocitopenia/inducido químicamenteRESUMEN
Elevated plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and large amounts of monocyte procoagulant activity (PCA) have been documented in unstable angina (UA) patients. In in vitro experiments heparin is able to blunt monocyte TF production by inhibiting TF and cytokine gene expression by stimulated cells and after in vivo administration it reduces adverse ischemic outcomes in UA patients. TF and TFPI plasma levels and monocyte PCA have been investigated in 28 refractory UA patients before and during anticoagulant subcutaneous heparin administration (thrice daily weight- and PTT-adjusted for 3 days) followed by 5000 IU X 3 for 5 days. After 2-day treatment, immediately prior to the heparin injection, TF and TFPI plasma levels [(median and range): 239 pg/ml, 130-385 pg/ ml and 120 ng/ml, 80-287 ng/ml] were lower in comparison to baseline samples (254.5 pg/ml, 134.6-380 pg/ml and 135.5 ng/ml, 74-306 ng/ml). Four h after the heparin injection TF furtherly decreased (176.5 pg/ml, 87.5-321 pg/ml; -32.5%. p<0.001) and TFPI increased (240.5 ng/ml, 140-450 ng/ml; +67%, p<0.0001). After 7-day treatment, before the injection of heparin, TF and TFPI plasma levels (200 pg/ml, 128-325 pg/ml and 115 ng/ml, 70-252 ng/ml) significantly decreased (p<0.05) in comparison to the pre-treatment values. On the morning of the 8th day, 4 h after the injection of heparin TF plasma levels and monocytes PCA significantly decreased (156.5 pg/ml, 74-259 pg/ml and from 180 U/105 monocytes, 109-582 U/10(5) monocytes to 86.1 U/10(5) monocytes, 28-320 U/10(5) monocytes; - 38% and -55% respectively) and TFPI increased (235.6 ng/ml, 152-423 ng/ ml; +70%, p<0.001). In conclusion, heparin treatment is associated with a decrease of high TF plasma levels and monocyte procoagulant activity in UA patients. These actions of heparin may play a role in determining the antithrombotic and antiinflammatory properties of this drug.
Asunto(s)
Hemostáticos/metabolismo , Heparina/administración & dosificación , Lipoproteínas/metabolismo , Tromboplastina/metabolismo , Adulto , Anciano , Angina Inestable/sangre , Anticoagulantes/sangre , Anticoagulantes/metabolismo , Factores de Coagulación Sanguínea , Femenino , Hemostáticos/sangre , Humanos , Leucocitos Mononucleares/química , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Monocitos/fisiología , Oxidación-Reducción , Factores de TiempoRESUMEN
Several studies have shown that n-3 polyunsaturated fatty acids (n-3 PUFA) are able to lower blood pressure (BP) in humans, but large doses of fish oils have been often used. Moreover, most of the studies available in the literature were not able to evaluate the specific effects of n-3 PUFA because they employed fish oils which contain, together with n-3 PUFA, many other different components. The aim of this preliminary study was to evaluate if medium-term supplementation with a moderate dose of highly purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters is able to reduce BP in mild hypertensive patients. Sixteen mild essential hypertensive (diastolic BP: 95-104 mm Hg), non-diabetic, normolipidemic male outpatients and 16 normotensive male controls were recruited to participate in the study. Both hypertensive and control subjects were randomly assigned to receive either EPA and DHA ethyl esters (2.04 g EPA and 1.4 g DHA) as active treatment or olive oil (4 g/day) as a placebo for a period of 4 months. These subjects were followed up with 24-hour ambulatory BP monitoring and blood chemistry analyses at 2 and 4 months of treatment and 2 months after its discontinuation. The intake of n-3 PUFA was checked by red blood cell (RBC) phosphatidylcholine (PC) fatty acid composition. The effect of n-3 PUFA on BP in the active group was maximum after 2 months. Both systolic (-6 mm Hg, p<0.05) and diastolic (-5 mm Hg, p<0.05) BP significantly decreased during the n-3 PUFA ethyl ester supplementation. No further effect was observed at 4 months with a return to baseline values during the recovery period. These data indicate that 4 g/day of highly purified EPA + DHA ethyl esters are able to favorably affect BP in mild hypertensives.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Hipertensión/tratamiento farmacológico , Adulto , Monitoreo Ambulatorio de la Presión Arterial , Grasas Insaturadas en la Dieta/administración & dosificación , Método Doble Ciego , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Aceite de Oliva , Aceites de Plantas/administración & dosificaciónRESUMEN
In addition to its well-understood anticoagulant activity, heparin is known to modulate a variety of biological functions including immunologic responses. In order to investigate whether heparin influences the humoral immunity by interacting with cellular elements and affecting gene expression in blood circulating cells. we studied the effect of heparin on IL-1beta, IL-6 and TNFalpha mRNAs in human lipopolysaccharide-(LPS)- or interferon-gamma(IFN-gamma)-stimulated mononuclear cells. The study of mRNA was carried out by an initial PCR screening followed by a Northern blot quantitative analysis. Heparin (0.5 U/ml) turned out to inhibit all three cytokine gene expressions. The mRNA decrease was 37 +/- 6% for IL-1beta, 53 +/- 3% for IL-6 and 47 +/- 4% for TNFalpha with LPS stimulus. No differences could be observed in the inhibitory effect of heparin on IFNgamma-stimulated cells. This effect of heparin was confirmed in a subset of experiments performed on purified monocytes. These results suggest an important immunosuppressive effect of heparin on cell-mediated immune responses.
Asunto(s)
Anticoagulantes/farmacología , Citocinas/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Heparina/farmacología , Interferón gamma/farmacología , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/farmacología , Células Cultivadas , Citocinas/inmunología , Antagonismo de Drogas , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-1/biosíntesis , Interleucina-6/biosíntesis , Leucocitos Mononucleares/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Several studies have shown that thrombosis and inflammation play an important role in the pathogenesis of Ischaemic Heart Disease (IHD). In particular, Tissue Factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key role in triggering thrombin generation. The aim of this study was to evaluate the TF/Tissue Factor Pathway Inhibitor (TFPI) system in patients with IHD. We have studied 55 patients with IHD and not on heparin [18 with unstable angina (UA), 24 with effort angina (EA) and 13 with previous myocardial infarction (MI)] and 48 sex- and age-matched healthy volunteers, by measuring plasma levels of TF, TFPI, Prothrombin Fragment 1-2 (F1+2), and Thrombin Antithrombin Complexes (TAT). TF plasma levels in IHD patients (median 215.4 pg/ml; range 72.6 to 834.3 pg/ml) were significantly (p<0.001) higher than those found in control subjects (median 142.5 pg/ml; range 28.0-255.3 pg/ml). Similarly, TFPI plasma levels in IHD patients were significantly higher (median 129.0 ng/ml; range 30.3-316.8 ng/ml; p<0.001) than those found in control subjects (median 60.4 ng/ml; range 20.8-151.3 ng/ml). UA patients showed higher amounts of TF and TFPI plasma levels (TF median 255.6 pg/ml; range 148.8-834.3 pg/ml; TFPI median 137.7 ng/ml; range 38.3-316.8 ng/ml) than patients with EA (TF median 182.0 pg/ml; range 72.6-380.0 pg/ml; TFPI median 115.2 ng/ml; range 47.0-196.8 ng/ml) and MI (TF median 213.9 pg/ml; range 125.0 to 341.9 pg/ml; TFPI median 130.5 ng/ml; range 94.0-207.8 ng/ml). Similar levels of TF and TFPI were found in patients with mono- or bivasal coronary lesions. A positive correlation was observed between TF and TFPI plasma levels (r = 0.57, p<0.001). Excess thrombin formation in patients with IHD was documented by TAT (median 5.2 microg/l; range 1.7-21.0 microg/l) and F1+2 levels (median 1.4 nmol/l; range 0.6 to 6.2 nmol/l) both significantly higher (p<0.001) than those found in control subjects (TAT median 2.3 microg/l; range 1.4-4.2 microg/l; F1+2 median 0.7 nmol/l; range 0.3-1.3 nmol/l). As in other conditions associated with cell-mediated clotting activation (cancer and DIC), also in IHD high levels of circulating TF are present. Endothelial cells and monocytes are the possible common source of TF and TFPI. The blood clotting activation observed in these patients may be related to elevated TF circulating levels not sufficiently inhibited by the elevated TFPI plasma levels present.
Asunto(s)
Lipoproteínas/sangre , Isquemia Miocárdica/sangre , Tromboplastina/metabolismo , Adulto , Angina Inestable/sangre , Coagulación Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Trombina/metabolismoRESUMEN
A growing body of evidence supports the existence of a tissue-based renin-angiotensin system (RAS) in the vasculature, but the functional capacity of vascular RAS was not investigated in humans. In 28 normotensive healthy control subjects, the metabolism of angiotensins through vascular tissue was investigated in normal, low, and high sodium diets by the measurement of arterial-venous gradient of endogenous angiotensin (Ang) I and Ang II in two different vascular beds (forearm and leg), combined with the study of 125I-Ang I and 125I-Ang II kinetics. In normal sodium diet subjects, forearm vascular tissue extracted 36+/-6% of 125I-Ang I and 30+/-5% of 125I-Ang II and added 14.9+/-5.1 fmol x 100 mL(-1) x min(-1) of de novo formed Ang I and 6.2+/-2.8 fmol x 100 mL(-1) x min(-1) of Ang II to antecubital venous blood. Fractional conversion of 125I-Ang I through forearm vascular tissue was about 12%. Low sodium diet increased (P<.01) plasma renin activity, whereas de novo Ang I and Ang II formation by forearm vascular tissue became undetectable. Angiotensin degradation (33+/-7% for Ang I and 30+/-7% for Ang II) was unchanged, and vascular fractional conversion of 125I-Ang I decreased from 12% to 6% (P<.01). In high sodium diet subjects, plasma renin activity decreased, and de novo Ang I and Ang II formation by forearm vascular tissue increased to 22 and 14 fmol x 100 mL(-1) x min(-1), respectively (P<.01). Angiotensin degradation did not significantly change, whereas fractional conversion of 125I-Ang I increased from 12% to 20% (P<.01). Leg vascular tissue functional activities of RAS paralleled those of forearm vascular tissue both at baseline and during different sodium intake. These results provide consistent evidence for the existence of a functional tissue-based RAS in vascular tissue of humans. The opposite changes of plasma renin activity and vascular angiotensin formation indicate that vascular RAS is independent from but related to circulating RAS.
Asunto(s)
Angiotensina II/efectos de los fármacos , Angiotensina I/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Sodio en la Dieta/farmacología , Adulto , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Método Doble Ciego , Femenino , Antebrazo/irrigación sanguínea , Humanos , Pierna/irrigación sanguínea , Masculino , Sistema Renina-Angiotensina/fisiología , Sodio en la Dieta/administración & dosificaciónRESUMEN
The relationship between impaired baroreflex sensitivity (BS) and the degree of sympathetic activation during exercise in patients with heart failure (HF) has not been studied in detail. For this purpose, we studied BS and measured plasma norepinephrine (NE) at rest, and during and after treadmill exercise in 15 patients and 10 controls. HF patients showed lower BS in comparison to controls (3. 51 +/- 3.62 vs. 9.74 +/- 4.56 ms/mm Hg; p < 0.001), and higher levels of plasma NE at rest (449.3 +/- 147.1 vs. 261.1 +/- 82.48 pg/ml; p < 0.001) and during exercise (1,542 +/- 361.2 vs. 524.6 +/- 92.61 pg/ml; p < 0.001). BS was directly related to pVO2 (r = 0.62; p = 0.0008) and inversely related to NE at peak exercise and to the increase in NE during exercise (r = 0.59, p = 0.005, and r = 0.53; p = 0.0058). Thus, during exercise, a marked sympathetic activation exists in patients with moderate HF. The relationship between increased plasma NE during exercise and decreased BS suggests that impaired baroreceptor function may be present in sympathetic activation in HF patients.
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Barorreflejo/fisiología , Cardiomiopatía Dilatada/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Presión Sanguínea/fisiología , Cardiomiopatía Dilatada/sangre , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Consumo de Oxígeno/fisiología , Maniobra de Valsalva/fisiologíaRESUMEN
Plasma endothelin (ET-1) and renal endothelin are two distinct functional systems involved in maintaining blood volume. To investigate whether plasma and renal ET-1 participate in the cardiovascular response to exercise-induced hypovolaemia, we studied changes in plasma and urinary ET-1 in healthy non-professional athletes after 2 h of jogging performed both without and with drinking isotonic fluids. After the run, which caused a 13% plasma volume (PV) reduction, plasma and renal ET-1 (+117% and +118%) increased significantly (all P < 0.01). Fluid loss restitution during the run significantly attenuated either the PV contraction (-1.2%) and plasma and renal ET-1 increase (+2 and +3%). At multiple regression analysis changes in AVP plasma concentration, and not in PRA or PV per se, were significantly related to ET-1 changes both in plasma and urine. The present findings indicate that both plasma and renal ET-1 participate in the cardiovascular response to hypovolaemia induced by long-lasting, dynamic exercise.
Asunto(s)
Volumen Sanguíneo , Endotelina-1/sangre , Endotelina-1/orina , Riñón/química , Esfuerzo Físico/fisiología , Adulto , Peso Corporal , Humanos , Soluciones Isotónicas/administración & dosificación , Masculino , Análisis de Regresión , Renina/sangre , Equilibrio HidroelectrolíticoRESUMEN
BACKGROUND: Recent studies suggest a role for inflammation in the pathophysiology of unstable angina. This study was designed to investigate whether circulating lymphocytes are involved in the inflammatory reaction associated with the episodes of unstable angina. METHODS AND RESULTS: Twenty-nine patients with proven unstable angina, 36 with stable angina, and 30 healthy subjects were studied. Both early and short-lived (interleukin-2 receptor [IL-2R], alpha-chain CD25, and transferrin receptor CD71) and late antigen (HLA-DR) expression were investigated by flow cytometric analysis. Soluble IL-2R (sIL-2R) was also measured in plasma by ELISA. Lymphocyte activation was studied at day 1 of hospital admission and after 7, 15, 30, 60, and 90 days. In patients with unstable angina, the number of HLA-DR+ CD3 lymphocytes and levels of sIL-2R were higher (P < .001) than in patients with stable angina and control subjects. Both CD4+ and CD8+ lymphocytes expressed HLA-DR antigens. No differences were found among the different groups of subjects in regard to the expression of CD25 and CD71. Lymphocyte activation was more marked in patients with urgent revascularization. No relationships were found between the number of HLA-DR+ lymphocytes and either the severity of coronary angiographic lesions or the number of ischemic episodes. Observations over time showed a gradual decrease in the number of HLA-DR+ lymphocytes and sIL-2R levels from weeks 3 through 8 to 12. CONCLUSIONS: The present results indicate that (1) CD4+ and CD8+ circulating lymphocytes are activated in patients with unstable angina, and their activation state lasts 6 to 8 weeks; and (2) activation of lymphocytes is not a consequence of myocardial ischemia. These results support the immune system-mediated inflammatory nature of unstable angina.
Asunto(s)
Angina Inestable/inmunología , Activación de Linfocitos , Subgrupos de Linfocitos T/inmunología , Anciano , Angina de Pecho/inmunología , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Arteriosclerosis/complicaciones , Arteriosclerosis/diagnóstico por imagen , Arteriosclerosis/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Angiografía Coronaria , Femenino , Antígenos HLA-DR/análisis , Humanos , Inflamación , Masculino , Persona de Mediana EdadRESUMEN
Renal formation of the vasoconstrictor prostaglandins thromboxane A2 (TXA2) and prostaglandin F2 alpha (PGF2 alpha) was investigated in 25 patients with cardiac failure, divided into New York Heart Association functional classes I to IV, and in eight healthy control subjects. Plasma renin activity (PRA) and hemodynamic parameters were also investigated. Renal vasoconstrictor eicosanoid formation, measured in urinary daily excretion, was not different between patients in class I and control subjects. Class II to IV patients showed progressively increasing production of PGF2 alpha (F = 49.8, p < 0.001, analysis of variance) and TXA2 (F = 37.8, p < 0.002). PGF2 alpha excretion peaked in class IV (+ 1266% vs class I, p < 0.001). Compared with class I, urinary excretion of thromboxane B2 was + 816% in class III and + 1561% in class IV (both p < 0.001). PRA was significantly increased only in class IV (+ 1558%, p < 0.001). The current results indicate a progressive increase in renal production of vasoconstrictor eicosanoids directly related to New York Heart Association class and suggest that these prostanoids may have a role in deterioration of renal function.
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Dinoprost/biosíntesis , Insuficiencia Cardíaca/orina , Riñón/metabolismo , Tromboxano A2/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Estudios de Casos y Controles , Dinoprost/orina , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Humanos , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Tromboxano A2/orinaRESUMEN
Stimulated monocytes are involved in blood clotting and fibrin dissolution by synthesizing tissue factor (TF) and fibrinolytic components such as plasminogen activator inhibitor type 2 (PAI-2). Heparin interacts with smooth muscle cells, platelets, and endothelial cells and specifically binds to human monocytes. In endothelial and smooth muscle cells, heparin selectively inhibits collagenase and tissue plasminogen activator gene expression. To investigate (1) heparin's influence on the hemostatic system by its interactions with plasma factors and cellular elements and (2) to determine its effects on gene expression in blood circulating cells, we studied the effect of heparin on TF and PAI-2 protein and mRNA in human lipopolysaccharide (LPS)- or interferon-gamma (IFN-gamma)-stimulated monocytes. TF and PAI-2 proteins were investigated by ELISA and by assaying procoagulant activity. The mRNA study was carried out by an initial PCR screening followed by a Northern blot semiquantitative analysis. Heparin (0.5 U/mL) inhibited both TF and PAI-2 production and gene expression. The contemporaneous protein and mRNA decrease (TF and PAI-2 protein 22 and 42%, respectively; suggests that this action is, at least partially, at the transcriptional level. The effect is not specific for heparin and is not demonstrated by other glycosaminoglycans (chondroitin-4-sulfate or dermatan sulfate). This action may be relevant for the antithrombotic activity of heparin in cell-mediated blood clotting activation.
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Anticoagulantes/farmacología , Heparina/farmacología , Leucocitos Mononucleares/metabolismo , Inhibidor 2 de Activador Plasminogénico/biosíntesis , Inhibidores de Serina Proteinasa/biosíntesis , Tromboplastina/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/efectos de los fármacos , Humanos , Lipopolisacáridos/farmacología , Inhibidor 2 de Activador Plasminogénico/genética , ARN Mensajero/metabolismo , Inhibidores de Serina Proteinasa/genética , Tromboplastina/genética , Transcripción Genética/efectos de los fármacosRESUMEN
BACKGROUND: The presence of mRNA for the essential components of the renin-angiotensin system (RAS) has been found in animal and human hearts. The present study was designed to provide evidence for the existence of a (functional) cardiac RAS. METHODS AND RESULTS: Twenty-four patients with atypical chest pain undergoing coronary angiography for diagnostic purposes were investigated. The cardiac production rate of angiotensins was estimated by measurement of the cardiac extraction of 125I-angiotensin I and 125I-angiotensin II associated with the determination of endogenous angiotensins in aortic and coronary sinus blood in normal, low, or high sodium diets. In a normal sodium diet, angiotensin I and II aorta-coronary sinus gradients were tendentially negative (-1.8 +/- 2.5 and -0.9 +/- 1.7 pg/mL, respectively), and the amounts of angiotensin I and II added by cardiac tissues were 6.5 +/- 3.1 and 2.7 +/- 1.3 pg/mL, respectively. The low sodium diet caused a significant increase in both plasma renin activity (PRA) and angiotensin I concentration in aortic but not in coronary sinus blood, resulting in a more negative aorta-coronary sinus gradient (-9.7 +/- 3.1 pg/mL, P < .01). Angiotensin formation by PRA in blood during transcardiac passage increased (P < .001), whereas angiotensin I formed by cardiac tissues decreased dramatically. Accordingly, in the low sodium diet, 125I-angiotensin II extraction did not change, the cardiac fractional conversion rate of 125I-angiotensin I to 125I-angiotensin II notably decreased (P < .01), and angiotensin II formation by cardiac tissues was undetectable. The high sodium diet caused a decrease in PRA and no changes in cardiac extraction of radiolabeled angiotensins; conversely, angiotensin I formed by cardiac tissues, cardiac Ang I fractional conversion rate, and angiotensin II formed during transcardiac passage significantly (P < .01 for all) increased. CONCLUSIONS: These results provide evidence for the existence of a functional cardiac RAS independent of but related to the circulating RAS.
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Miocardio/metabolismo , Sistema Renina-Angiotensina/fisiología , Adulto , Angiotensina I/sangre , Angiotensina I/farmacocinética , Angiotensina II/sangre , Angiotensina II/farmacocinética , Angiotensinas/análisis , Cromatografía Líquida de Alta Presión , Circulación Coronaria , Dieta Hiposódica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/química , Fragmentos de Péptidos/análisis , Distribución TisularRESUMEN
n-3 polyunsaturated fatty acids (PUFA) can affect several monocyte functions and the biochemistry of blood cells, thus possibly influencing the initiation of thrombosis, inflammatory disease and atherosclerosis. In this study, we have investigated the effect of dietary supplementation with n-3 PUFA ethyl esters on procoagulant activity (PCA) and interleukin-6 (IL-6) production by human mononuclear cells. Nine healthy volunteers received 4 g/d of n-3 PUFA ethyl esters (4 x 1 g capsules with at least 85% eicosapentaenoic + docosahexaenoic acid ethyl esters) for 18 weeks. Before and at the end of the treatment, mononuclear cells were obtained from peripheral citrated blood by Ficoll-Hypaque density gradient centrifugation. Cellular suspensions (10(7) cells/ml) were incubated at 37 degrees C for 4 h in the absence and presence of lipopolysaccharide (10 micrograms/ml); PCA was determined by one-stage clotting assay and IL-6 concentrations were assayed in supernatants by specific ELISA. After 18-week treatment, both unstimulated and stimulated monocyte PCA were significantly reduced by 66% and 63%, respectively (P < 0.01). Similarly, a significant inhibitory effect by n-3 PUFA treatment on basal and LPS-stimulated IL-6 monocyte production was observed (50% and 46%, respectively, P < 0.05). These data indicate that 18-week n-3 PUFA supplementation may influence monocyte activities, which play a specific role in atherosclerosis and its thrombotic complications.