RESUMEN
OBJECTIVE: To investigate the effects of preventive angiotensin converting enzyme inhibitor treatment with ramipril in dogs with progressively severe experimentally induced heart failure. ANIMALS: 20 dogs. PROCEDURES: Dogs were randomly allocated to receive no treatment (control) or ramipril (0.125 mg/kg, PO, daily) for 7 weeks. Physical examination, repetitive catheterization of the right side of the heart, and echocardiography were performed before the study (day 0) and weekly for 7 weeks. Renal plasma flow (RPF) as determined by para-aminohippuric acid clearance and glomerular filtration rate (GFR) as determined by creatinine and iohexol clearances were measured on day 0 and at weeks 4 and 7. RESULTS: Overpacing induced a progressive increase in right atrial pressure (RAP) and pulmonary artery pressure, occluded (PAPO), with a decrease in systemic arterial pressure. There were progressive alterations of echocardiographic indices of diastolic and systolic ventricular function. The RPF and GFR decreased before cardiac output decreased, and filtration fraction increased. The logarithm of the urinary sodium-to-potassium concentration ratio (log(10)[Na(+)/K(+)]) decreased. Significant effects of ramipril included a delay in clinical signs of heart failure, a late decrease in RAP and PAPO, and increases in the sodium excretion fraction and log(10)(Na(+)/K(+)). There was a satisfactory agreement between the creatinine and iohexol clearance measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that, in this rapid-evolving, dilated cardiomyopathy, activation of the renin-angiotensin system contributes to the pathophysiology of heart failure late in the disease and essentially by an activation of renal salt and water retention.
Asunto(s)
Enfermedades de los Perros/tratamiento farmacológico , Insuficiencia Cardíaca/veterinaria , Ramipril/uso terapéutico , Circulación Renal/efectos de los fármacos , Flujo Plasmático Renal/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Perros , Masculino , Factores de TiempoRESUMEN
Endothelin receptor antagonists (ERAs) have been developed to block the effects of endothelin-1 (ET-1) in a variety of cardiovascular conditions. ET-1 is a powerful vasoconstrictor with mitogenic or co-mitogenic properties, which acts through the stimulation of 2 subtypes of receptors [endothelin receptor subtype A (ETA) and endothelin receptor subtype B (ETB) receptors]. Endogenous ET-1 is involved in a variety of conditions including systemic and pulmonary hypertension (PH), congestive heart failure (CHF), vascular remodeling (restenosis, atherosclerosis), renal failure, cancer, and cerebrovascular disease. The first dual ETA/ETB receptor blocker, bosentan, has already been approved by the Food and Drug Administration for the treatment of pulmonary arterial hypertension (PAH). Trials of endothelin receptor antagonists in heart failure have been completed with mixed results so far. Studies are ongoing on the effects of selective ETA antagonists or dual ETA/ETB antagonists in lung fibrosis, cancer, and subarachnoid hemorrhage. While non-peptidic ET-1 receptor antagonists suitable for oral intake with excellent bioavailability have become available, proven efficacy is limited to pulmonary hypertension, but it is possible that these agents might find a place in the treatment of several cardiovascular and non-cardiovascular diseases in the coming future.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Animales , Antihipertensivos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismoRESUMEN
Heart failure is associated with autonomic imbalance, and this can be evaluated by a spectral analysis of heart rate variability. However, the time course of low-frequency (LF) and high-frequency (HF) heart rate variability changes, and their functional correlates during progression of the disease are not exactly known. Progressive heart failure was induced in 16 beagle dogs over a 7-wk period by rapid ventricular pacing. Spectral analysis of heart rate variability and respiration, echocardiography, hemodynamic measurements, plasma atrial natriuretic factor, and norepinephrine was obtained at baseline and every week, 30 min after pacing interruption. Progressive heart failure increased heart rate (from 91 +/- 4 to 136 +/- 5 beats/min; P < 0.001) and decreased absolute and normalized (percentage of total power) HF variability from week 1 and 2, respectively (P < 0.01). Absolute LF variability did not change during the study until it disappeared in two dogs at week 7 (P < 0.05). Normalized LF variability increased in moderate heart failure (P < 0.01), leading to an increased LF-to-HF ratio (P < 0.05), but decreased in severe heart failure (P < 0.044; week 7 vs. week 5). Stepwise regression analysis revealed that among heart rate variables, absolute HF variability was closely associated with wedge pressure, right atrial and pulmonary arterial pressure, left ventricular ejection fraction and volume, ratio of maximal velocity of early (E) and atrial (A) mitral flow waves, left atrial diameter, plasma norepinephrine, and atrial natriuretic peptide (0.45 < r < 0.65, all P < 0.001). In tachycardia-induced heart failure, absolute HF heart rate variability is a more reliable indicator of cardiac dysfunction and neurohumoral activation than LF heart rate variability.
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Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/fisiología , Mecánica Respiratoria/fisiología , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Perros , Masculino , Sistema Nervioso Parasimpático/fisiología , Sistema Nervioso Simpático/fisiología , Taquicardia/fisiopatologíaRESUMEN
BACKGROUND: Halogenated anesthetics depress left ventricular function, but their effects on the right ventricle have been less well studied. Therefore, the authors studied the effects of isoflurane and desflurane on pulmonary arterial (PA) and right ventricular (RV) properties at baseline and in hypoxia. METHODS: Right ventricular and PA pressures were measured by micromanometer catheters, and PA flow was measured by an ultrasonic flow probe. PA mechanics were assessed by flow-pressure relations and by impedance spectra derived from flow and pressure waves. RV contractility was assessed by end-systolic elastance (Ees), RV afterload was assessed by effective PA elastance (Ea), and RV-PA coupling efficiency was assessed by the Ees:Ea ratio. Anesthetized dogs were randomly assigned to increasing concentrations (0.5, 1, and 1.5 times the minimum alveolar concentration) of isoflurane (n = 7) or desflurane (n = 7) in hyperoxia (fraction of inspired oxygen, 0.4) and hypoxia (fraction of inspired oxygen, 0.1). RESULTS: Isoflurane and desflurane had similar effects. During hyperoxia, both anesthetics increased PA resistance and characteristic impedance, increased Ea (isoflurane, from 0.82 to 1.44 mmHg/ml; desflurane, from 0.86 to 1.47 mmHg/ml), decreased Ees (isoflurane, from 1.09 to 0.66 mmHg/ml; desflurane, from 1.10 to 0.72 mmHg/ml), and decreased Ees:Ea (isoflurane, from 1.48 to 0.52; desflurane, from 1.52 to 0.54) in a dose-dependent manner (all P < 0.05). Hypoxia increased PA resistance, did not affect characteristic impedance, increased afterload, and increased contractility. During hypoxia, isoflurane and desflurane had similar ventricular effects as during hyperoxia. CONCLUSIONS: Isoflurane and desflurane markedly impair RV-PA coupling efficiency in dogs, during hyperoxia and hypoxia, both by increasing RV afterload and by decreasing RV contractility.
Asunto(s)
Anestésicos por Inhalación/toxicidad , Corazón/efectos de los fármacos , Isoflurano/análogos & derivados , Isoflurano/toxicidad , Arteria Pulmonar/efectos de los fármacos , Animales , Análisis de los Gases de la Sangre , Desflurano , Perros , Ventrículos Cardíacos/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Hiperoxia/fisiopatología , Hipoxia/fisiopatología , Arteria Pulmonar/fisiología , Resistencia Vascular/efectos de los fármacos , Función Ventricular Derecha/efectos de los fármacosRESUMEN
BACKGROUND: The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II. CONCLUSIONS: Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.
Asunto(s)
Angiopoyetina 1/fisiología , Hipertensión Pulmonar/prevención & control , Inhibidores de Fosfodiesterasa/uso terapéutico , Piperazinas/uso terapéutico , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/efectos de los fármacos , 3',5'-GMP Cíclico Fosfodiesterasas , Anastomosis Quirúrgica/efectos adversos , Angiopoyetina 1/biosíntesis , Angiopoyetina 1/genética , Angiotensina II/biosíntesis , Angiotensina II/genética , Animales , Arteriolas/ultraestructura , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1 , Receptores de Proteínas Morfogenéticas Óseas de Tipo II , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Evaluación Preclínica de Medicamentos , Endotelina-1/biosíntesis , Endotelina-1/genética , Regulación de la Expresión Génica/efectos de los fármacos , Hiperplasia , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Modelos Animales , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/biosíntesis , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Hidrolasas Diéster Fosfóricas/genética , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Arteria Pulmonar/cirugía , Purinas , ARN Mensajero/biosíntesis , Distribución Aleatoria , Receptores de Factores de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento/genética , Citrato de Sildenafil , Arteria Subclavia/cirugía , Sulfonas , Sus scrofa , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
OBJECTIVE: A transient increase in pulmonary arterial (PA) pressure can persistently depress right ventricular (RV) contractility. We investigated the effects norepinephrine and dobutamine on RV-PA coupling in this model of RV failure. DESIGN: Prospective, controlled, randomized animal study. SETTING: University research laboratory. SUBJECTS: Twenty-two anesthetized dogs. INTERVENTIONS: Animals underwent transient (90-min) PA constriction to induce persistent RV failure. They were randomly assigned to control, norepinephrine, or dobutamine group. Norepinephrine was administered at 0.1 and 0.5 microg x kg x min or dobutamine at 5 and 10 microg x kg x min. MEASUREMENTS AND MAIN RESULTS: We measured PA distal resistance and proximal elastance by pressure-flow relationships and vascular impedance. We also measured RV contractility by the end-systolic pressure-volume relationship (Ees), PA effective elastance by the end-diastolic to end-systolic relationship (Ea), and RV-PA coupling efficiency by the Ees/Ea ratio. The transient PA constriction persistently increased PA resistance and elastance, increased Ea from 0.8+/-0.1 to 2.7+/-0.3 mmHg/mL, decreased Ees from 1.1+/-0.1 to 0.5+/-0.1 mm Hg/mL, and decreased Ees/Ea from 1.2+/-0.1 to 0.2+/-0.1. Norepinephrine restored arterial pressure, increased RV contractility, and increased but did not normalize RV-PA coupling and cardiac output. Dobutamine restored arterial pressure, markedly increased RV contractility, and normalized RV-PA coupling and cardiac output. Compared with norepinephrine, dobutamine decreased PA resistance and elastance and increased RV contractility and RV-PA coupling. CONCLUSIONS: A transient increase in PA pressure persistently worsens PA hemodynamics, RV contractility, RV-PA coupling, and cardiac output. Dobutamine restores RV-PA coupling and cardiac output better than norepinephrine because of its more pronounced inotropic effect.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Cardiotónicos/farmacología , Dobutamina/farmacología , Hipertensión Pulmonar/fisiopatología , Contracción Miocárdica/efectos de los fármacos , Norepinefrina/farmacología , Volumen Sistólico/efectos de los fármacos , Disfunción Ventricular Derecha/fisiopatología , Animales , Presión Sanguínea/fisiología , Perros , Contracción Miocárdica/fisiología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Presión Esfenoidal Pulmonar/fisiología , Volumen Sistólico/fisiología , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiologíaRESUMEN
We investigated the time course of the expression of cardiac and renal endothelin systems in tachycardia-induced heart failure in dogs. Eleven beagles underwent rapid pacing at a progressively increased rate over a period of 5 wk, with a weekly clinical examination, echocardiography, measurement of circulating and urinary endothelin-1 (ET-1), and myocardial and renal tissue biopsies. Real-time quantitative PCR was used for determinations of tissue prepro-ET-1 (ppET-1), ET-1-converting enzyme (ECE-1), and ETA and ETB receptor mRNA. Cardiac and renal tissue ET-1 contents were evaluated by immunostaining and measured by radioimmunoassay at autopsy. Rapid pacing caused a progressive increase in end-systolic and end-diastolic ventricular volumes (P < 0.05) from week 2 together with a decrease in ejection fraction and in mean velocity of circumferential shortening (P < 0.05) from week 1. These changes were tightly correlated to myocardial ppET-1 and renal ETA receptor mRNA and less so to myocardial ECE-1 mRNA, and they occurred before any increase in plasma and urinary ET-1 (P < 0.05 from week 4) and clinical signs of heart failure. Renal ppET-1 did not change. Both cardiac and renal ET-1 peptide contents were increased at autopsy. We conclude that tachycardia-induced heart failure in dogs is characterized by an early activation of the cardiac and renal tissue endothelin systems, which occurs before any changes in circulating and urinary ET-1 and is closely related to altered ventricular function.
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Insuficiencia Cardíaca/fisiopatología , Riñón/fisiopatología , Miocardio/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Biopsia , Presión Sanguínea , Perros , Endotelina-1/sangre , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-1/orina , Enzimas Convertidoras de Endotelina , Expresión Génica/fisiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Frecuencia Cardíaca , Riñón/metabolismo , Riñón/patología , Masculino , Metaloendopeptidasas , Marcapaso Artificial , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , RespiraciónRESUMEN
BACKGROUND: The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET(B) receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET(A) receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan. CONCLUSIONS: Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.