RESUMEN
BACKGROUND: We developed a noninvasive method to examine coronary flow reserve with technetium 99m tetrofosmin based on the microsphere model. According to the microsphere model, myocardial blood flow (MBF) can be calculated by MBF = q / integral C(t)dt, where q is myocardial activity and C(t) is tracer concentration in blood. Because the ratio of integral C(t)dt at stress to rest is equal to the ratio of the first transit count in the pulmonary artery (PA) and attenuation factors were canceled out, we calculated the increase ratio of MBF (MBF(IR)). METHODS AND RESULTS: After injection of dipyridamole, tetrofosmin was injected as a bolus and serial dynamic planar images were obtained to measure the first transit count in PA (PAC). Myocardial single photon emission computed tomography was performed to measure the regional myocardial count (RMC). MBF(IR) was calculated as [(RMCs x PACr)/(RMCr x PACs) - 1] x 100, where r and s denote resting and stress conditions, respectively. In contrast, the increase in the myocardial uptake ratio (MUR(IR)) was defined as (RMCs x SCr/RMCr x SCs - 1) x 100, where SC is syringe count of tracer. The results were as follows: (1) The mean MBF of healthy subjects was 46.9% +/- 22.8%. (2) MBF(IR) of the infarcted region and ischemic region was significantly decreased (8.3% +/- 12.2% and 11.2% +/- 11.9%, respectively; P <.001). (3) MUR(IR) was significantly lower than MBF(IR) (14.1% +/- 21.2%; P <.001). (4) MBF(IR) decreased according to the heart rate at rest (r = 0.47; P <.05). CONCLUSIONS: MBF(IR) is a potential parameter with which to evaluate coronary flow reserve when the changes of arterial input function during stress are considered.
Asunto(s)
Circulación Coronaria , Corazón/diagnóstico por imagen , Compuestos Organofosforados , Compuestos de Organotecnecio , Tomografía Computarizada de Emisión de Fotón Único , HumanosRESUMEN
BACKGROUND--Endothelin (ET)-1 is generated from big ET-1 by endothelin-converting enzyme (ECE). Plasma big ET-1 and ET-1 levels are strongly related to survival in patents with congestive heart failure (CHF). Because selective enzymatic processing of ET-1 formation appears to be an important therapeutic target for CHF, we investigated the acute effects of a specific ECE inhibitor on cardiorenal and endocrine functions in CHF compared with those of a selective ETA receptor antagonist. METHODS AND RESULTS--CHF was induced in beagle dogs by rapid right ventricular pacing (270 bpm, 14 days). Two incremental doses of a specific ECE inhibitor, FR901533, or a selective ETA receptor antagonist, FR139317 (1 and 3 mg/kg, n=8, respectively), were injected into dogs with CHF. FR901533 and FR139317 decreased mean arterial pressure and pulmonary capillary wedge pressure associated with reduction in systemic and pulmonary vascular resistance. These agents increased cardiac output but did not affect left ventricular fractional shortening. FR139317 exerted a greater depressor effect on mean arterial pressure than FR901533 (P<0.05). These agents decreased plasma atrial natriuretic peptide levels, but only FR901533 decreased plasma renin activity, angiotensin II, and aldosterone levels. Neither agent changed the plasma norepinephrine level despite the fall in blood pressure. These drugs increased the urinary water and sodium excretion rate associated with increases in the glomerular filtration rate and renal plasma flow, and the incremental magnitude induced by FR139317 was larger than that by FR901533 (P<0.05). CONCLUSIONS--An ETA receptor antagonist appeared to induce greater vasodilative effects on systemic and renal vasculature in CHF than an ECE inhibitor. However, the ECE inhibitor reduced the secretion of neurohumoral factors that are activated in proportion to the severity of CHF. Our acute complementary data may support the importance of the role of ECE in CHF and provide a rationale foundation for investigating the usefulness of long-term treatment with ECE inhibitors in CHF.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Azepinas/farmacología , Antagonistas de los Receptores de Endotelina , Endotelina-1/metabolismo , Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Indoles/farmacología , Tetraciclinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Endotelina-1/sangre , Endotelina-1/orina , Femenino , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Neuropéptidos/efectos de los fármacos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Receptor de Endotelina A , Factores de Tiempo , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: Both the selective endothelin (ET) ETA receptor and mixed ETA/ETB receptor antagonists improve haemodynamics in patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ETA receptor and mixed ETA/ETB receptor antagonists in CHF. METHODS: We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days. RESULTS: Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels. CONCLUSIONS: These ETA/ETB antagonist. However, the long-term administration of a mixed ETA/ETB receptor antagonist would improve not only the haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.
Asunto(s)
Azepinas/uso terapéutico , Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Indoles/uso terapéutico , Riñón/efectos de los fármacos , Péptidos Cíclicos/uso terapéutico , Aldosterona/sangre , Análisis de Varianza , Animales , Factor Natriurético Atrial/sangre , Estimulación Cardíaca Artificial , Perros , Endotelina-1/farmacología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Riñón/fisiopatología , Masculino , Receptor de Endotelina A , Flujo Plasmático Renal/efectos de los fármacos , Sodio/orinaRESUMEN
Early-stage heart failure (HF) is characterized by an increase in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS) or body fluid retention. To test the hypothesis that elevated endogenous ANP suppresses the RAAS, maintains body fluid balance, and regulates vascular tone in early-stage HF, we assessed the effects of short-term and long-term inhibition of ANP on cardiorenal and neurohormonal functions. Short-term antagonism was produced by bolus administration (3 mg/kg) of HS-142-1, an antagonist of guanylate-cyclase coupled ANP receptors, and long-term antagonism was produced by continuous infusion (1 mg/kg per h) of HS-142-1 for 8 h to dogs with early-stage HF induced by rapid ventricular pacing (270 beats/min, 8 days). In this experimentally produced HF, plasma ANP was significantly increased relative to the pre-pacing value, but not plasma renin activity (PRA) or plasma aldosterone level. HS-142-1 significantly suppressed plasma and urinary guanosine 3',5'-cyclic monophosphate (cGMP) levels, markers of endogenous ANP activity, in both experiments. Although mean arterial pressure and cardiac output did not change significantly, pulmonary capillary wedge pressure and right atrial pressure were elevated in both experiments. While short-term inhibition of ANP did not change PRA and aldosterone levels, long-term inhibition significantly increased these hormonal levels, resulting in decreases in urine flow rate, urinary sodium excretion rate, glomerular filtration rate, and renal plasma flow. These findings suggest that endogenous ANP plays a critical role in regulating venovascular tone, inhibiting activation of RAAS, and maintaining renal functions in early-stage HF.
Asunto(s)
Factor Natriurético Atrial/sangre , Insuficiencia Cardíaca/fisiopatología , Sistema Renina-Angiotensina/fisiología , Animales , Perros , Insuficiencia Cardíaca/sangre , Hemodinámica , Polisacáridos/farmacología , Receptores del Factor Natriurético Atrial/antagonistas & inhibidores , Receptores del Factor Natriurético Atrial/fisiologíaRESUMEN
Endothelin (ET)-1 increases in plasma during congestive heart failure (CHF). Some ET antagonists improve hemodynamics, suggesting its potential benefits in the treatment of CHF. We examined the acute and chronic effects of a new ET receptor antagonist, T-0201 (Tanabe Seiyaku Co. Ltd., Japan), in CHF. To confirm the in vivo effects of T-0201, we observed the inhibitory effects of T-0201 (1-100 micrograms/kg) on the response of blood pressure to exogenously administered ET-1 (0.75 nmol/kg) in conscious normal dogs. Pretreatment with T-0201 significantly inhibited the ET-1-induced initial hypotension that is mediated by ETB receptors, and attenuated the subsequent hypertension, which is primarily mediated by ETA receptors. Thus, T-0201 at a dose of 100 micrograms/kg not only works as a potent ETA antagonist but also shows antagonist activity for ETB receptors in dogs. To evaluate the chronic therapeutic effects of T-0201, we administered T-0201 (0.3 mg/kg/day; n = 5) orally to dogs with CHF induced by rapid right ventricular pacing (22 days, 270 beats/min) for 15 days, beginning 8 days after pacing. T-0201 significantly prevented the deterioration of cardiorenal function during the development of CHF, expressed as a decrease in cardiac pressure and an increase in cardiac and urine output. These results suggest that chronic antagonism of both ET receptors prevents the progressive exacerbation of CHF.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Estimulación Cardíaca Artificial , Enfermedad Crónica , Perros , Endotelina-1/antagonistas & inhibidores , Endotelina-1/farmacología , Insuficiencia Cardíaca/fisiopatología , Presión Esfenoidal Pulmonar/efectos de los fármacos , Urodinámica/efectos de los fármacosRESUMEN
OBJECTIVES: We 1) evaluated whether interleukin-6 (IL-6) is produced in the peripheral circulation in patients with congestive heart failure (CHF), 2) estimated the factors for increased IL-6, and 3) clarified the prognostic role of high plasma levels of IL-6 in patients with CHF. BACKGROUND: Although plasma levels of IL-6 have been reported to increase in patients with CHF, and production of IL-6 in endothelial cells and vascular smooth muscle cells has been postulated from in vitro studies, the origin of the increase of IL-6 in CHF remains unknown. Moreover, the prognostic value of a high plasma level of IL-6, independent of classic neurohumoral factors, remains to be elucidated. METHODS: A comparison was made of the plasma levels of IL-6 between the femoral artery and the femoral vein in 13 normal subjects and in 80 patients with CHF. In another study, we measured plasma IL-6 in 100 patients with CHF and follow-up data. RESULTS: Plasma IL-6 levels increased significantly from the femoral artery to the femoral vein in normal subjects and in patients with CHF. Arteriovenous IL-6 spillover in the leg increased with the severity of CHF. Among the hemodynamic variables and the various neurohumoral factors, the plasma norepinephrine (NE) level showed an independent and significant positive relation with the plasma IL-6 level in patients with CHF. Moreover, treatment with beta-adrenergic blocking agents showed an independent and significant negative relation with plasma IL-6 levels. In 100 patients, plasma IL-6 (p < 0.0001), NE (p = 0.0004) and left ventricular ejection fraction (0.015) were significant independent prognostic predictors by Cox proportional hazards analysis. CONCLUSIONS: Our findings indicate that the IL-6 spillover in the peripheral circulation increases with the severity of CHF and that the increase in plasma IL-6 is mainly associated with the activation of the sympathetic nervous system. High plasma levels of IL-6 can provide prognostic information in patients with CHF, independent of left ventricular ejection fraction and plasma NE, suggesting an important role for IL-6 in the pathophysiology of CHF.
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Insuficiencia Cardíaca/sangre , Interleucina-6/sangre , Agonistas alfa-Adrenérgicos/sangre , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Factor Natriurético Atrial/sangre , Estudios de Casos y Controles , Endotelina-1/sangre , Endotelio Vascular/metabolismo , Femenino , Arteria Femoral , Vena Femoral , Estudios de Seguimiento , Predicción , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Interleucina-6/biosíntesis , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/metabolismo , Neurotransmisores/sangre , Norepinefrina/sangre , Pronóstico , Modelos de Riesgos Proporcionales , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Sistema Nervioso Simpático/fisiopatología , Simpatomiméticos/sangre , Factor de Necrosis Tumoral alfa/análisis , Vasoconstrictores/sangre , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiologíaRESUMEN
Ouabain can cause increased secretion of atrial natriuretic peptide (ANP) from atrial cardiocyte culture, but the effects of digitalis in a therapeutic range on the secretion of cardiac natriuretic peptide including ANP and brain natriuretic peptide (BNP), mainly from the ventricle, in patients with congestive heart failure remain to be investigated. Therefore we studied the acute effects of intravenous infusion of a relatively low dose of digitalis or placebo on hemodynamics and neurohumoral factors including the plasma levels of ANP and BNP and cyclic guanosine monophosphate, a second messenger of cardiac natriuretic peptide, in 13 patients with severe congestive heart failure. No significant change in the hemodynamic parameters or neurohumoral factors was observed with placebo. After 1 hour of intravenous administration of deslanoside (0.01 mg/kg), there was a significant decrease of plasma renin activity and angiotensin II, aldosterone, and norepinephrine levels but no significant change of plasma levels of vasopressin and a significant decrease of the pulmonary capillary wedge pressure but no significant change in cardiac index. In addition, plasma levels of ANP (217 +/- 47 vs 281 +/- 70 pg/ml, p < 0.05), BNP (628 +/- 116 vs 689 +/- 132 pg/ml, p < 0.05), and cyclic guanosine monophosphate (9.7 +/- 1.1 vs 10.9 +/- 1.5 pmol/ml, p < 0.05) increased despite the decrease of pulmonary capillary wedge pressure (19.7 +/- 2.3 vs 16.8 +/- 2.3 mm Hg, p < 0.05). These results indicate the acute intravenous low dose of digitalis resulted in a significant increase in plasma levels of ANP, BNP, and cyclic guanosine monophosphate concomitant with the significant decrease of pulmonary capillary wedge pressure, suggesting the acute direct action of digitalis on the cardiac natriuretic peptides released from the heart in patients with severe congestive heart failure.
Asunto(s)
Factor Natriurético Atrial/sangre , Cardiotónicos/farmacología , Deslanosido/farmacología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Proteínas del Tejido Nervioso/sangre , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Cardiotónicos/administración & dosificación , Deslanosido/administración & dosificación , Femenino , Guanosina Monofosfato/sangre , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Péptido Natriurético Encefálico , Norepinefrina/sangre , Renina/sangreRESUMEN
OBJECTIVES: This study was designed 1) to determine the extent to which endogenous endothelin (ET) affects hemodynamic, hormonal and body fluid balance through ETA and ETB receptors in congestive heart failure (CHF); and 2) to assess the therapeutic benefits and adverse effects of ET receptor antagonists for ETA and ETB on cardiorenal and neurohormonal variables. BACKGROUND: ET has two receptors, ETA and ETB, both of which are distributed in various tissues and cells. In vascular beds, ETA receptors mediate vasoconstriction, whereas ETB receptors mediate vasorelaxation. However, ETB receptors also exist in smooth muscle and mediate vasoconstriction. METHODS: We administered either the ETA receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETB receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing. The effects of both antagonists on cardiorenal and hormonal functions were studied. RESULTS: FR decreased cardiac pressures and the plasma atrial natriuretic peptide (ANP) level and increased cardiac output (CO). Urinary flow rate and urinary sodium excretion increased in association with an increase in the glomerular filtration rate and renal plasma flow (RPF). In contrast, RES increased cardiac pressures and decreased CO. It also decreased the plasma aldosterone level and RPF. Neither antagonist affected plasma norepinephrine levels. CONCLUSIONS: Endogenous ETs increase cardiac pressures and the retention of body fluid through ETA receptors in CHF. The vasodilative action through ETB receptors is overall functionally more important than the constrictive action through ETB receptors. ETs may regulate the secretion of ANP and aldosterone. Our findings suggest that selective ETA receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETB receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF.
Asunto(s)
Azepinas/farmacología , Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/fisiopatología , Indoles/farmacología , Péptidos Cíclicos/farmacología , Análisis de Varianza , Animales , Factor Natriurético Atrial/sangre , Gasto Cardíaco/efectos de los fármacos , Perros , Femenino , Corazón/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , Masculino , Urodinámica/efectos de los fármacosRESUMEN
BACKGROUND: Patients with congestive heart failure (CHF) have high plasma levels of atrial natriuretic peptide (ANP), mainly from the atrium, and brain natriuretic peptide (BNP), mainly from the ventricle. We examined the prognostic role of plasma BNP in chronic CHF patients in comparison with plasma ANP and other variables previously known to be associated with high mortality. We also evaluated the relationship between mortality and plasma cGMP, a biological marker of ANP and BNP. METHODS AND RESULTS: The study subjects were 85 patients with chronic CHF (left ventricular ejection fraction <0.45) who were followed for 2 years. The plasma levels of ANP, BNP, cGMP, and norepinephrine increased with the severity of CHF. Among plasma levels of ANP, BNP, cGMP, and norepinephrine and clinical and hemodynamic parameters, only high levels of plasma BNP (P<.0001) and pulmonary capillary wedge pressure (P=.003) were significant independent predictors of the mortality in patients with CHF by Cox proportional hazard analysis. Although plasma levels of ANP and BNP were threefold or fivefold higher in nonsurvivors than in survivors, there was no difference in plasma cGMP level between nonsurvivors and survivors. CONCLUSIONS: These findings indicate that plasma BNP is more useful than ANP for assessing the mortality in patients with chronic CHF and that the plasma levels of BNP provide prognostic information independent of other variables previously associated with a poor prognosis. Our findings also suggest that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Proteínas del Tejido Nervioso/sangre , Función Ventricular Izquierda , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Enfermedad Crónica , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico , PronósticoRESUMEN
To evaluate the effects of endogenous angiotensin II (ANG II) on the development of congestive heart failure (CHF), we examined cardiorenal and hormonal factors after chronic administration of the ANG II type 1 receptor antagonist TCV-116 in dogs with CHF induced by rapid right ventricular pacing. After 8 days of pacing, TCV-116 administration [1 (group 1) or 3 mg.kg-1.day-1 (group 2)] was started and continued until the 22nd day. TCV-116 was found to have protected the deterioration of cardiorenal functions and the activation of neurohormonal factors. Although there was no significant difference in the pulmonary capillary wedge pressure or plasma atrial natriuretic peptide (ANP) level between the TCV-116-treated groups (354 +/- 85 and 364 +/- 29 pg/ml for groups 1 and 2, respectively) and the vehicle group (385 +/- 20 pg/ml), the plasma guanosine 3',5'-cyclic monophosphate (cGMP) levels, a second messenger of ANP, were twofold higher in TCV-116-treated groups (49.4 +/- 10.2 and 50.6 +/- 7.7 pmol/ml for groups 1 and 2, respectively) than in the vehicle group (24 +/- 4.0 pmol/ml), with a high correlation between the plasma ANP and cGMP levels (r = 0.90; P < 0.05). These findings indicate that endogenous ANG II has important roles in hemodynamics and renal functions during the development of CHF, which may be due, in part, to a reduction in endogenous ANP activity, suggesting the usefulness of an ANG II-receptor antagonist against the development of CHF.
Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Factor Natriurético Atrial/sangre , Bencimidazoles/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , GMP Cíclico/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles , Aldosterona/sangre , Animales , Antihipertensivos/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , GMP Cíclico/sangre , GMP Cíclico/orina , Perros , Femenino , Tasa de Filtración Glomerular , Hemodinámica , Riñón/fisiología , Masculino , Norepinefrina/sangre , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Factores de Tiempo , Resistencia VascularRESUMEN
We tested the hypothesis that plasma endothelin-1 (ET-1) and soluble intercellular adhesion molecule-1 (sICAM-1) in patients with congestive heart failure (CHF) are related to subsequent survival, and assessed whether the measurements of these substances provide additional prognostic information to that obtained from clinical and biochemical variables previously known to be associated with high mortality. Plasma levels of sICAM-1 and ET-1 were measured in 102 patients with CHF (left ventricular ejection fraction [LVEF] < 0.45), and patients were followed up for > 18 months. The plasma level of sICAM-1 increased with the severity of CHF (normal, 149 +/- 10 ng/ml, mild CHF [New York Heart Association functional class II], 207 +/- 9.4 ng/ml, severe CHF [functional class III or IV], 293 +/- 18 ng/ml). The plasma level of ET-1 also increased with the severity of CHF (normal, 1.5 +/- 0.2 pg/ml, mild CHF, 2.1 +/- 0.1 pg/ml, severe CHF, 4.0 +/- 0.4 pg/ml). Plasma levels of both sICAM-1 and ET-1 decreased after treatment in 14 patients, with improvements in symptoms (from functional class IV to II) during the follow-up period. There was a significant positive correlation between the plasma level of ET-1 and plasma sICAM-1 (r = 0.44, p < 0.001). A significant negative correlation was observed between LVEF and plasma ET-1 (r = -0.34, p < 0.001), and plasma sICAM-1 (r = -0.36, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endotelinas/sangre , Insuficiencia Cardíaca/sangre , Molécula 1 de Adhesión Intercelular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Solubilidad , Volumen Sistólico , Tasa de SupervivenciaRESUMEN
Hemodynamic tolerance has been observed within several hours of continuous infusion of nitroglycerin (NTG). We examined the hemodynamic parameters as well as femoral arterial and venous cyclic guanosine monophosphate (cGMP) concentrations during intravenous infusion of NTG or nicorandil, a nitrate and potassium channel opener, in patients with congestive heart failure. Doses of NTG or nicorandil were titrated to achieve a > or = 25% reduction in pulmonary capillary wedge pressure (PCWP) within 1 hour, and the infusion was maintained at a constant rate for 24 hours. The reduction in PCWP and mean arterial blood pressure was identical after a 1-hour infusion of either NTG or nicorandil. In the NTG group, PCWP and mean blood pressure were not significantly different from the baseline value at 12 hours, but in the nicorandil group PCWP and mean blood pressure remained significantly lower than the preinfusion value for 24 hours. The cGMP production with NTG (assessed by the difference between the plasma arterial and venous cGMP level) paralleled the changes in PCWP, suggesting that the plasma arteriovenous cGMP difference is a biochemical indicator of nitrate tolerance. Although the sustained decrease in PCWP was observed in the nicorandil group, cGMP production with nicorandil was also attenuated at 24 hours of continuous infusion. These findings suggest that the absence of the hemodynamic tolerance of nicorandil, a nitrate and potassium channel opener, is likely due to its action as a potassium channel opener, and not to its nitrate activity.