RESUMEN
BACKGROUND: Pigs/bovines share with humans some of the antigens present on cardiac valves. Two such antigens are: the major xenogenic Ag, "Gal" present in all pig/bovine very close to human B-antigen of ABO-blood-group system; the minor Ag, pig histo-blood-group AH-antigen identical to human AH-antigen and present by some animals. We hypothesize that these antigens may modify the immunogenicity of the bioprosthesis and also its longevity. ABO distribution may vary between patients with low (<6â¯years) and high (≥15â¯years) bioprostheses longevity. METHODS: Single-centre registry study (Paris, France) including all degenerative porcine bioprostheses (mostly Carpentier-Edwards 2nd/3rd generation heart valves) explanted between 1985 and 1998 and some bovine bioprostheses. For period 1998-2014, all porcine bioprostheses with longevity ≥13â¯years (follow-up ≥29â¯years). Important predictive factors for bioprosthesis longevity: number, site of implantation, age were collected. Blood group and other variables were entered into an ordinal logistic regression analysis model predicting valve longevity, categorized as low (<6â¯years), medium (6-14.9â¯years), and high (≥15â¯years). FINDINGS: Longevity and ABO-blood group were obtained for 483 explanted porcine bioprostheses. Mean longevity was 10.2⯱â¯3.9â¯years [0-28] and significantly higher for A-patients than others (Pâ¯=â¯0.009). Using multivariate analysis, group A was a strong predictive factor of longevity (OR 2.09; Pâ¯<â¯0.001). For the 64 explanted bovine bioprosthesis with low/medium longevity, the association, with A-group was even more significant. INTERPRETATION: Patients of A-group but not B have a higher longevity of their bioprostheses. Future graft-host phenotyping and matching may give rise to a new generation of long-lasting bioprosthesis for implantation in humans, especially for the younger population. FUND: None.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Implantación de Prótesis de Válvulas Cardíacas , Tasa de Supervivencia , Receptores de Trasplantes , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Bovinos , Niño , Femenino , Francia/epidemiología , Encuestas Epidemiológicas , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Humanos , Longevidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Sistema de Registros , Porcinos , Adulto JovenRESUMEN
Complex 3D beating heart models are now available, but their complexity makes calibration and validation very difficult tasks. We thus propose a systematic approach of deriving simplified reduced-dimensional models, in "0D"-typically, to represent a cardiac cavity, or several coupled cavities-and in "1D"-to model elongated structures such as muscle samples or myocytes. We apply this approach with an earlier-proposed 3D cardiac model designed to capture length-dependence effects in contraction, which we here complement by an additional modeling component devised to represent length-dependent relaxation. We then present experimental data produced with rat papillary muscle samples when varying preload and afterload conditions, and we achieve some detailed validations of the 1D model with these data, including for the length-dependence effects that are accurately captured. Finally, when running simulations of the 0D model pre-calibrated with the 1D model parameters, we obtain pressure-volume indicators of the left ventricle in good agreement with some important features of cardiac physiology, including the so-called Frank-Starling mechanism, the End-Systolic Pressure-Volume Relationship, as well as varying elastance properties. This integrated multi-dimensional modeling approach thus sheds new light on the relations between the phenomena observed at different scales and at the local versus organ levels.
Asunto(s)
Corazón/fisiología , Modelos Cardiovasculares , Algoritmos , Animales , Presión Sanguínea , Calibración , Simulación por Computador , Elasticidad , Ventrículos Cardíacos , Imagenología Tridimensional , Contracción Miocárdica/fisiología , Miocardio/patología , Ratas , Reproducibilidad de los Resultados , Sarcómeros/fisiología , Función Ventricular IzquierdaRESUMEN
INTRODUCTION: Human placental stem villi (PSV) present contractile properties. We studied the role of actin-myosin cross bridges (CBs) and the effects of NO-cGMP pathway modulators in the PSV contraction and relaxation. METHODS: In vitro contractile properties were investigated in 71 PSV from term human placentas studied according to their long axis. Contraction was induced by both KCl and electrical tetanic stimulation. Relaxation was induced by inhibiting the CB cycle with either 2,3-butanedione monoxime (BDM) or blebbistatin (BLE) and by activating the NO-cGMP pathway with isosorbide dinitrate (ISDN), sildenafil (SIL) or ISDN + SIL. RESULTS: PSV tension slowly increased by 140% of the basal tone after KCl exposure and by 85% after tetanus. The addition of BDM, BLE, ISDN, SIL and ISDN + SIL induced a relaxation of PSV, the overall time course of relaxation (in s) was respectively (means ± SD) 3412 ± 1904, 14,250 ± 3095*, 3813 ± 1383, 2883 ± 1188 and 2440 ± 477; significantly longer in BLE compared with BDM, ISDN, SIL and ISDN + SIL:*p < 0.001). the overall time course of relaxation (in s) was respectively (means ± SD) 3412 ± 1904, 14,250 ± 3095*, 3813 ± 1383, 2883 ± 1188 and 2440 ± 477; significantly longer in BLE compared with BDM, ISDN, SIL and ISDN + SIL:*p < 0.001). These relaxation kinetics were particularly slow. Other relaxation parametres, i.e., maximum lengthening, -peak dT/dt, and resting tension, did not differ between these 5 subgroups. DISCUSSION AND CONCLUSION: Isolated human PSV were able to contract after both KCl exposure and tetanus. This increase in contractility was reversed by inhibiting the CB cycle with BDM or BLE and by stimulating the NO-cGMP pathway with ISDN or SIL. The association ISDN + SIL did not potentiate the relaxing processes.
Asunto(s)
Actinas/fisiología , Vellosidades Coriónicas/fisiología , GMP Cíclico/fisiología , Miosinas/fisiología , Óxido Nítrico/fisiología , Sistemas de Mensajero Secundario , Actinas/antagonistas & inhibidores , Actinas/química , Vellosidades Coriónicas/química , Vellosidades Coriónicas/efectos de los fármacos , GMP Cíclico/agonistas , GMP Cíclico/antagonistas & inhibidores , Diacetil/análogos & derivados , Diacetil/farmacología , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Técnicas In Vitro , Dinitrato de Isosorbide/farmacología , Cinética , Miosinas/antagonistas & inhibidores , Miosinas/química , Óxido Nítrico/agonistas , Óxido Nítrico/antagonistas & inhibidores , Donantes de Óxido Nítrico/farmacología , Piperazinas/farmacología , Docilidad/efectos de los fármacos , Cloruro de Potasio/metabolismo , Embarazo , Estructura Cuaternaria de Proteína , Purinas/farmacología , Sistemas de Mensajero Secundario/efectos de los fármacos , Citrato de Sildenafil , Sulfonas/farmacología , Nacimiento a TérminoRESUMEN
The current study was designed to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain is associated with impaired spontaneous relaxation of airway smooth muscle. Strips of the posterior portion of the trachea from 10 adult Fisher and 10 adult Lewis rats were electrically stimulated at pH 7.4, 2.5 mM Ca(2+)concentration, at 37 degrees C. Both isotonic and isometric relaxations of tracheal smooth muscle (TSM) were investigated. Half time for isotonic relaxation at preload was markedly prolonged in Fisher rats (8.33+/-3.21 s) compared with Lewis rats (3.53+/-0.54 s; p<0.001). Maximum lengthening velocity at preload and peak rate of isometric tension decline were significantly decreased in Fisher rats compared with Lewis rats. The ratio of shortening velocity to lengthening velocity at preload, as well as the ratio of the isometric peak rates of tension development to tension decline were higher in Fisher rat TSM than in Lewis rat TSM. These differences were associated with a six-fold higher expression of myosin light chain kinase in Fisher rats than in Lewis rats. In Fisher rats, these results suggest that innate airway hyperresponsiveness is associated with both a reduced level and a slower rate of TSM spontaneous relaxation, promoting maintenance of airway constriction.
Asunto(s)
Hiperreactividad Bronquial/fisiopatología , Relajación Muscular , Músculo Liso/patología , Tráquea/patología , Animales , Calcio/metabolismo , Electrofisiología/métodos , Concentración de Iones de Hidrógeno , Masculino , Quinasa de Cadena Ligera de Miosina/metabolismo , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Especificidad de la Especie , Factores de TiempoRESUMEN
In vitro isotonic and isometric mechanical properties of the sternohyoid (SH) muscle, an upper airway dilator muscle, were studied in rats with a growth hormone (GH)-secreting tumour (GH tumour group; n = 10). The effects of muscle fatigue were also studied. Stress and shortening were measured in muscles contracting from zero load up to isometric load under tetanic conditions. Isometric stress and maximum unloaded shortening velocity were determined and compared with values obtained from control rats (n = 10). Crossbridge kinetics and energetics and mechanical efficiency were calculated from Huxley's equations. Compared with controls, isometric stress, mechanical efficiency, crossbridge number and crossbridge single force were lower in the GH tumour group. The probability of crossbridge being in the power stroke configuration was lower in the GH tumour group than in controls. Muscle fatigue significantly impaired maximal muscle efficiency and crossbridge single force in the GH tumour group but not in controls. In conclusion, mechanical and energetic properties of the SH muscle and crossbridge properties were worse in the GH tumour group than in controls. This may partly account for impairment of the upper airway dilator muscle function and the increased occurrence of obstructive sleep apnoea in acromegaly.
Asunto(s)
Acromegalia/fisiopatología , Hormona del Crecimiento/sangre , Contracción Isométrica/fisiología , Músculos del Cuello/fisiología , Síndromes de la Apnea del Sueño/fisiopatología , Acromegalia/complicaciones , Acromegalia/metabolismo , Adenoma/complicaciones , Adenoma/metabolismo , Adenoma/fisiopatología , Animales , Peso Corporal , Línea Celular Tumoral , Modelos Animales de Enfermedad , Metabolismo Energético/fisiología , Femenino , Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/fisiopatología , Fatiga Muscular/fisiología , Miosinas/metabolismo , Trasplante de Neoplasias , Ratas , Ratas Endogámicas WF , Síndromes de la Apnea del Sueño/etiología , Síndromes de la Apnea del Sueño/metabolismoRESUMEN
BACKGROUND: Cardiac tissue engineering might be useful in treatment of diseased myocardium or cardiac malformations. The creation of functional, biocompatible contractile tissues, however, remains challenging. We hypothesized that coupling of arginine-glycine-aspartic acid-serine (RGD+) adhesion peptides would improve cardiomyocyte viability and differentiation and contractile performance of collagen-cell scaffolds. METHODS: Clinically approved collagen scaffolds were functionalized with RGD+ cells and seeded with cardiomyocytes. Contractile performance, cardiomyocyte viability and differentiation were analyzed at days 1 and 8 and/or after culture for 1 month. RESULTS: The method used for the RGD+ cell-collagen scaffold coupling enabled the following features: high coupling yields and complete washout of excess reagent and by-products with no need for chromatography; spectroscopic quantification of RGD+ coupling; a spacer arm of 36 A, a length reported as optimal for RGD+-peptide presentation and favorable for integrin-receptor clustering and subsequent activation. Isotonic and isometric mechanical parameters, either spontaneous or electrostimulated, exhibited good performance in RGD+ constructs. Cell number and viability was increased in RGD+ scaffolds, and we saw good organization of cell contractile apparatus with occurrence of cross-striation. CONCLUSIONS: We report a novel method of engineering a highly effective collagen-cell scaffold based on RGD+ peptides cross-linked to a clinically approved collagen matrix. The main advantages were cell contractile performance, cardiomyocyte viability and differentiation.
Asunto(s)
Materiales Biocompatibles , Diferenciación Celular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Oligopéptidos/química , Adhesión Celular/efectos de los fármacos , Colágeno , Humanos , Ingeniería de TejidosRESUMEN
Peroxisome proliferator activated receptor alpha (PPAR alpha) regulates fatty acid beta-oxidation (FAO) and plays a central role in the metabolic and energetic homeostasis of striated muscles. The thermodynamic consequences of the absence of PPAR alpha were investigated in diaphragm muscle of PPAR alpha knockout mice (KO). Statistical mechanics provides a powerful tool for determining entropy production, which quantifies irreversible chemical processes generated by myosin molecular motors and which is the product of thermodynamic force A/T (chemical affinity A and temperature T) and thermodynamic flow (myosin crossbridge (CB) cycle velocity upsilon). The behavior of both wild type (WT) and KO diaphragm was shown to be near-equilibrium and in a stationary state, but KO was farther from equilibrium than WT. In KO diaphragm, a substantial decrease in contractile function was associated with an increase in both A/T and upsilon and with profound histological injuries such as contraction band necrosis. There were no changes in PPAR delta and gamma expression levels or myosin heavy chain (MHC) patterns. In KO diaphragm, a marked increase in entropy production (A/T x upsilon) accounted for major thermodynamic dysfunction and a dramatic increase in irreversible chemical processes during the myosin CB cycle.
Asunto(s)
Diafragma/fisiopatología , PPAR alfa/deficiencia , Animales , Peso Corporal , Diafragma/metabolismo , Diafragma/patología , Entropía , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Cadenas Pesadas de Miosina/análisis , Miosinas/metabolismo , PPAR alfa/biosíntesis , PPAR alfa/genética , PPAR delta/biosíntesis , PPAR delta/genética , PPAR gamma/biosíntesis , PPAR gamma/genética , Isoformas de Proteínas/análisis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , TermodinámicaRESUMEN
Statistical mechanics provides the link between microscopic properties of matter and its bulk properties. The grand canonical ensemble formalism was applied to contracting rat skeletal muscles, the soleus (SOL, n = 30) and the extensor digitalis longus (EDL, n = 30). Huxley's equations were used to calculate force (pi) per single crossbridge (CB), probabilities of six steps of the CB cycle, and peak muscle efficiency (Eff(max)). SOL and EDL were shown to be in near-equilibrium (CB cycle affinity 2.5 kJ/mol) and stationary state (linearity between CB cycle affinity and myosin ATPase rate). The molecular partition function (z) was higher in EDL (1.126+/-0.005) than in SOL (1.050+/-0.003). Both pi and Eff(max) were lower in EDL (8.3+/-0.1 pN and 38.1+/-0.2%, respectively) than in SOL (9.2+/-0.1 pN and 42.3+/-0.2%, respectively). The most populated step of the CB cycle was the last detached state (D3) (probability P(D3): 0.890+/-0.004 in EDL and 0.953+/-0.002 in SOL). In each muscle group, both pi and Eff(max) linearly decreased with z and statistical entropy and increased with P(D3). We concluded that statistical mechanics and Huxley's formalism provided a powerful combination for establishing an analytical link between chemomechanical properties of CBs, molecular partition function and statistical entropy.
Asunto(s)
Modelos Estadísticos , Proteínas Motoras Moleculares/fisiología , Músculo Esquelético/fisiología , Miosinas/metabolismo , Adenosina Trifosfatasas/metabolismo , Animales , Contracción Isométrica/fisiología , Modelos Biológicos , RatasRESUMEN
The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats. Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxley's equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (approximately 46% and approximately 42%, respectively), whereas peak isometric tension was similar. The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (approximately -46% and -34%, respectively). In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity.
Asunto(s)
Hiperreactividad Bronquial/genética , Contracción Muscular/genética , Músculo Liso/fisiología , Ratas Endogámicas F344/genética , Ratas Endogámicas Lew/genética , Tráquea/fisiología , Animales , Hiperreactividad Bronquial/fisiopatología , Cinética , Miosinas/genética , RatasRESUMEN
BACKGROUND: The effects of halogenated anaesthetics on cross-bridge (CB) kinetics are unclear. As halogenated anaesthetics do not markedly modify the intracellular calcium transient in the diaphragm, we used an isolated rat diaphragm preparation to assess the effects of halothane and isoflurane on CB kinetics. METHODS: The effects of halothane and isoflurane (1 and 2 minimum alveolar concentration (MAC)) on rat diaphragm muscle strips were studied in vitro (Krebs-Henseleit solution, 29 degrees C, oxygen 95%/carbon dioxide 5%) in tetanus mode (50 Hz). From the force-velocity curve and using A. F. Huxley's equations, we determined the main mechanical and energetic variables and calculated CB kinetics. RESULTS: At 1 and 2 MAC, isoflurane and halothane induced no significant inotropic effects. Whatever the concentrations tested, halothane and isoflurane did not significantly modify the CB number, the elementary force per CB, the attachment and detachment constants, the duration of the CB cycle and mean CB velocity. CONCLUSION: In the rat diaphragm at therapeutic concentrations, halogenated anaesthetics do not significantly modify CB mechanical and kinetic properties.
Asunto(s)
Actinas/metabolismo , Anestésicos por Inhalación/farmacología , Contracción Muscular/efectos de los fármacos , Miosinas/metabolismo , Animales , Técnicas de Cultivo , Diafragma/efectos de los fármacos , Diafragma/metabolismo , Halotano/farmacología , Isoflurano/farmacología , Ratas , Ratas WistarRESUMEN
Pulmonary hypertension is characterised by the chronic elevation of pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) leading to right ventricular enlargement and hypertrophy. Pulmonary hypertension may result from respiratory and cardiac diseases, the most severe forms occurring in thromboembolic and primary pulmonary hypertension. Pulmonary hypertension is most often defined as a mean PAP >25 mmHg at rest or >30 mmHg during exercise, the pressure being measured invasively with a pulmonary artery catheter. Doppler echocardiography allows serial, noninvasive follow-up of PAPs and right heart function. When the adaptive mechanisms of right ventricular dilatation and hypertrophy cannot compensate for the haemodynamic burden, right heart failure occurs and is associated with poor prognosis. The haemodynamic profile is the major determinant of prognosis. In both primary and secondary pulmonary hypertension, special attention must be paid to the assessment of pulmonary vascular resistance index (PVRI), right heart function and pulmonary vasodilatory reserve. Recent studies have stressed the prognostic values of exercise capacity (6-min walk test), right atrial pressure, stroke index and vasodilator challenge responses, as well as an interest in new imaging techniques and natriuretic peptide determinations. Overall, careful haemodynamic evaluation may optimise new diagnostic and therapeutic strategies in pulmonary hypertension.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Circulación Pulmonar , Presión Sanguínea , Cateterismo Cardíaco , Cateterismo de Swan-Ganz , Ecocardiografía Doppler , Prueba de Esfuerzo , Hemodinámica , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Arteria Pulmonar , Resistencia Vascular , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular DerechaRESUMEN
To analyze the kinetics and unitary force of cross bridges (CBs) in airway smooth muscle (ASM), we proposed a new formalism of Huxley's equations adapted to nonsarcomeric muscles (Huxley AF. Prog Biophys Biophys Chem 7: 255-318, 1957). These equations were applied to ASM from rabbits, rats, and humans (n = 12/group). We tested the hypothesis that species differences in whole ASM mechanics were related to differences in CB mechanics. We calculated the total CB number per square millimeter at peak isometric tension (Psi x10(9)), CB unitary force (Pi), and the rate constants for CB attachment (f(1)) and detachment (g(1) and g(2)). Total tension, Psi, and Pi were significantly higher in rabbits than in humans and rats. Values of Pi were 8.6 +/- 0.1 pN in rabbits, 7.6 +/- 0.3 pN in humans, and 7.7 +/- 0.2 pN in rats. Values of Psi were 4.0 +/- 0.5 in rabbits, 1.2 +/- 0.1 in humans, and 1.9 +/- 0.2 in rats; f(1) was lower in humans than in rabbits and rats; g(2) was higher in rabbits than in rats and in rats than in humans. In conclusion, ASM mechanical behavior of different species was characterized by specific CB kinetics and CB unitary force.
Asunto(s)
Modelos Biológicos , Músculo Liso/fisiología , Miosinas/fisiología , Tráquea/fisiología , Animales , Humanos , Cinética , Proteínas Motoras Moleculares/fisiología , Conejos , Ratas , Especificidad de la EspecieRESUMEN
Different classes of molecular motors, "rowers" and "porters," have been proposed to describe the chemomechanical transduction of energy. Rowers work in large assemblies and spend a large percentage of time detached from their lattice substrate. Porters behave in the opposite way. We calculated the number of myosin II cross bridges (CB) and the probabilities of attached and detached states in a minimal four-state model in slow (soleus) and fast (diaphragm) mouse skeletal muscles. In both muscles, we found that the probability of CB being detached was approximately 98% and the number of working CB was higher than 10(9)/mm(2). We concluded that muscular myosin II motors were classified in the category of rowers. Moreover, attachment time was higher than time stroke and time for ADP release. The duration of the transition from detached to attached states represented the rate-limiting step of the overall attached time. Thus diaphragm and soleus myosins belong to subtype 1 rowers.
Asunto(s)
Diafragma/fisiología , Proteínas Motoras Moleculares/fisiología , Músculo Esquelético/fisiología , Miosinas/fisiología , Animales , Contracción Isométrica/fisiología , Ratones , Modelos Biológicos , Factores de TiempoRESUMEN
BACKGROUND: Protamine alters the inotropic responses to beta-adrenoceptor stimulation, but its mechanism of action is not well-understood. Moreover, its interaction with alpha-adrenoceptor stimulation and the lusitropic (relaxation) response to beta-adrenoceptor stimulation remain unknown. METHODS: The effects of protamine (10 or 100 microg/ml) on the responses induced by phenylephrine and isoproterenol were studied in rat left ventricular papillary muscles. Inotropic and lusitropic effects were studied under low and high loads. The authors also studied the interaction of protamine with forskolin (50 microm) and dibutyryl 3',5'-cAMP (0.5 mm). Data are mean percentage of baseline active force +/- SD. RESULTS: In control groups, phenylephrine (135 +/- 17%, P < 0.05) and isoproterenol (185 +/- 44%, P < 0.05) induced a positive inotropic effect. Isoproterenol induced positive lusitropic effects under low and high loads. Protamine abolished the inotropic responses to alpha- (102 +/- 23%, not significant) and beta-adrenoceptor stimulations (99 +/- 17%, not significant) but did not modify the lusitropic responses to isoproterenol. Protamine abolished the inotropic responses to forskolin (89 +/- 6 vs. 154 +/- 20%, P < 0.05) and markedly decreased that of dibutyryl 3',5'-cAMP (132 +/- 31 vs. 167 +/- 30%, P < 0.05) but did not modify their lusitropic responses. CONCLUSIONS: Protamine abolished the inotropic responses to alpha- and beta-adrenoceptor stimulations but preserved the lusitropic responses to beta-adrenoceptor stimulation. Although protamine may act at several sites on the adrenoceptor stimulation cascade, one of its main sites of action is situated downstream from cAMP-mediated phosphorylation.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Relajación Muscular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Protaminas/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacos , Análisis de Varianza , Animales , Interacciones Farmacológicas , Ratas , Ratas WistarRESUMEN
Thiopental induces a negative inotropic effect on mammalian heart muscle, where it decreases Ca2+ current and Ca2+ release from the sarcoplasmic reticulum and reduces K+ currents. We analysed the effects of thiopental on the mechanical and electrical activities of rat myocardium, which differ markedly from those of other mammals. The effects of thiopental on mechanical parameters and on the transmembrane resting (RP) and action (AP) potentials of rat left ventricular papillary muscle were investigated. These effects were also studied in the presence of atenolol, a beta-blocking agent, and 4-aminopyridine (4-AP), a blocker of the transient outward K+ current. Thiopental (3.8 x 10(-6), 3.8 x 10(-5) and 1.1 x 10(-4) M) induced a dose-dependent positive inotropic effect. This positive inotropic effect persisted in the presence of atenolol (1 x 10(-6) M) but did not develop in the presence of 1 mM 4-AP; 4-AP had a positive inotropic effect but not in the presence of thiopental. Moreover, thiopental (3.8 x 10(-5) M) lengthened the plateau and the slow repolarizing phase of the AP, while 1 mM 4-AP only prolonged the plateau duration. In rat myocardium, the positive inotropic effect of thiopental in part mimics that of 4-AP, and in part may be explained by the lengthening of the slow repolarizing phase of the AP.
Asunto(s)
Anestésicos Intravenosos/farmacología , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Tiopental/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Técnicas de Cultivo , Relación Dosis-Respuesta a Droga , Potenciales de la Membrana/efectos de los fármacos , Músculos Papilares/fisiología , Ratas , Ratas Wistar , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
STUDY OBJECTIVES: Respiratory muscle strength has been shown to be reduced in patients with chronic heart failure. The purpose of this prospective study was to determine whether long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor perindopril improves respiratory muscle strength in patients with chronic heart failure. PATIENTS AND METHODS: Eighteen patients with stable chronic heart failure were administered perindopril, 4 mg/d, in addition to their standard therapy for a period of 6 months. Fourteen patients completed the study. Maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) expressed in percentage of predicted values, left ventricular ejection fraction (LVEF) determined by means of two-dimensional echocardiography, and pulmonary volumes were obtained before and after therapy. MEASUREMENTS AND RESULTS: As compared to baseline, there was a significant increase in both PImax and PEmax after therapy (57 +/- 27% predicted vs 78 +/- 36% predicted and 62 +/- 20% predicted vs 73 +/- 15% predicted, respectively; each p < 0.05). LVEF increased (34 +/- 5% vs 41 +/- 10%; p < 0.05); functional class improved by > or = 1 New York Heart Association (NYHA) class in five patients. There were no changes in pulmonary volumes. No correlation was found between changes in PImax and PEmax and changes in either LVEF or NYHA functional class. CONCLUSIONS: In patients with chronic heart failure, long-term therapy with the ACE inhibitor perindopril improved respiratory muscle strength, as indicated by significant increases in PImax and PEmax.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Perindopril/uso terapéutico , Músculos Respiratorios/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Enfermedad Crónica , Ecocardiografía , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Perindopril/administración & dosificación , Estudios Prospectivos , Músculos Respiratorios/fisiología , Volumen Sistólico/efectos de los fármacosRESUMEN
OBJECTIVES: The purpose of this time-domain study was to compare pulmonary artery (PA) pulse pressure and wave reflection in chronic pulmonary thromboembolism (CPTE) and primary pulmonary hypertension (PPH). BACKGROUND: Pulmonary artery pressure waveform analysis provides a simple and accurate estimation of right ventricular afterload in the time-domain. Chronic pulmonary thromboembolism and PPH are both responsible for severe pulmonary hypertension. Chronic pulmonary thromboembolism and PPH predominantly involve proximal and distal arteries, respectively, and may lead to differences in PA pressure waveform. METHODS: High-fidelity PA pressure was recorded in 14 patients (7 men/7 women, 46 +/- 14 years) with CPTE (n = 7) and PPH (n = 7). We measured thermodilution cardiac output, mean PA pressure (MPAP), PA pulse pressure (PAPP = systolic - diastolic PAP) and normalized PAPP (nPAPP = PPAP/MPAP). Wave reflection was quantified by measuring Ti, that is, the time between pressure upstroke and the systolic inflection point (Pi), deltaP, that is, the systolic PAP minus Pi difference, and the augmentation index (deltaP/PPAP). RESULTS: At baseline, CPTE and PPH had similar cardiac index (2.4 +/- 0.4 vs. 2.5 +/- 0.5 l/min/m2), mean PAP (59 +/- 9 vs. 59 +/- 10 mm Hg), PPAP (57 +/- 13 vs. 53 +/- 13 mm Hg) and nPPAP (0.97 +/- 0.16 vs. 0.89 +/- 0.13). Chronic pulmonary thromboembolism had shorter Ti (90 +/- 17 vs. 126 +/- 16 ms, p < 0.01) and higher deltaP/PPAP (0.26 +/- 0.01 vs. 0.09 +/- 0.07, p < 0.01). CONCLUSIONS: Our study indicated that: 1) CPTE and PPH with severe pulmonary hypertension had similar PA pulse pressure, and 2) wave reflection is elevated in both groups, and CPTE had increased and anticipated wave reflection as compared with PPH, thus suggesting differences in the pulsatile component of right ventricular afterload.
Asunto(s)
Presión Sanguínea , Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Embolia Pulmonar/fisiopatología , Pulso Arterial , Adulto , Cateterismo Cardíaco , Gasto Cardíaco , Enfermedad Crónica , Diástole , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Flujo Pulsátil , Resistencia VascularRESUMEN
UNLABELLED: We studied the effects of protamine (10-300 microg. mL(-1)) as well as its interaction with heparin in rat left ventricular papillary muscles in vitro at calcium concentrations of 0.5 and 1 mM under low (isotony) and high (isometry) loads. Protamine induced a negative inotropic effect that was less pronounced at calcium 0.5 mM (active force at protamine 300 microg/mL, 84 +/- 20 vs 57 +/- 15% of baseline, P: < 0.05); whereas at calcium 1 mM there was a marked contracture of the muscle. For the smallest concentrations of protamine and at calcium 0.5 mM, we observed a moderate positive inotropic effect that was suppressed by nifedipine. Protamine induced a negative lusitropic effect under low load and decreased postrest potentiation, suggesting an impairment in the functions of the sarcoplasmic reticulum. Heparin was able to inhibit and reverse the negative inotropic effect of protamine. The negative inotropic effect of protamine is enhanced by an increase in extracellular calcium concentration. This negative inotropic effect is probably related to calcium overload and impairment in sarcoplasmic reticulum functions, and heparin can block these effects. IMPLICATIONS: The negative inotropic effect of protamine is enhanced by an increase in extracellular calcium concentration. This negative inotropic effect is probably related to calcium overload and impairment in sarcoplasmic reticulum functions, and heparin can block these effects.
Asunto(s)
Calcio/farmacología , Antagonistas de Heparina/farmacología , Protaminas/farmacología , Animales , Anticoagulantes/farmacología , Cardiotónicos/farmacología , Espacio Extracelular/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Heparina/farmacología , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The present study investigates the mechanical and energetic changes induced by hypoxia in isolated cardiac muscles of different species characterized by different myosin isoforms. Classic mechanical parameters of contraction and energetic parameters derived from the tension-velocity relationship were studied in rat and guinea pig left ventricular papillary muscles and in frog ventricular strips before and after 15 min hypoxia (n = 8 in each group). The isomyosin pattern is predominantly V1 with high ATPase activity in rat and V3 with low ATPase activity in guinea pig and frog heart ventricles. At baseline, cardiac mechanical performance was greater in rat than in guinea pig and frog muscle, but the economy of tension generation did not differ significantly between the three species. Hypoxia significantly decreased myocardial mechanical performance in all three groups. Mechanical impairment was more marked in rat than in the other two species and was intermediate in guinea pig. The energetic consequences of hypoxia differed according to species and in a different manner from the mechanical parameters. Hypoxia decreased the economy of tension generation in rat heart, in contrast to no change in guinea pig and frog muscle. These results suggest that in terms of mechano-energetic properties, cardiac muscles with V1 isomyosin were more sensitive to hypoxia than those containing V3 isomyosin.
Asunto(s)
Hipoxia/fisiopatología , Contracción Miocárdica , Músculos Papilares/fisiopatología , Adenosina Trifosfatasas/metabolismo , Animales , Metabolismo Energético , Cobayas , Corazón/fisiopatología , Ventrículos Cardíacos , Miocardio/metabolismo , Miosinas/metabolismo , Isoformas de Proteínas/metabolismo , Rana esculenta , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
Mechanical studies of isolated muscle and analysis of molecular actomyosin interactions have improved our understanding of the pathophysiology of airway smooth muscle. Mechanical properties of airway smooth muscle are similar to those of other smooth muscles. Airway smooth muscle exhibits spontaneous intrinsic tone and its maximum shortening velocity (Vmax) is 10-30 fold lower than in striated muscle. Smooth muscle myosin generates step size and elementary force per crossbridge interaction approximately similar to those of skeletal muscle myosin. Special slow cycling crossbridges, termed latch-bridges, have been attributed to myosin light chain dephosphorylation. From a mechanical point of view, it has been shown that airway hyperresponsiveness is characterized by an increased Vmax and an increased shortening capacity, with no significant change in the force-generating capacity.