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1.
J Med Chem ; 64(11): 7691-7701, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34038119

RESUMEN

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.


Asunto(s)
Natriuréticos/química , Bloqueadores de los Canales de Potasio/química , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Animales , Benzofuranos/química , Presión Sanguínea/efectos de los fármacos , Diuréticos/química , Diuréticos/metabolismo , Diuréticos/farmacología , Perros , Semivida , Haplorrinos , Humanos , Masculino , Natriuréticos/metabolismo , Natriuréticos/farmacología , Piperazinas/química , Potasio/orina , Bloqueadores de los Canales de Potasio/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/metabolismo , Ratas , Ratas Endogámicas SHR
2.
Reprod Biol ; 18(1): 66-75, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29361408

RESUMEN

In our study, we added natriuretic peptide type C (NPPC) and/or sildenafil during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs) followed by in vitro culture (IVC) of embryos with or without sildenafil. We evaluated the effects on the lipid content (LC) of oocytes and embryos and also verified the expression of 96 transcripts related to competence in matured COCs and 96 transcripts related to embryo quality in blastocysts. After IVM, LC was decreased in oocytes by NPPC while sildenafil did not affect LC in oocytes. The genes involved in lipid metabolism and lipid accumulation (DGAT1, PLIN2and PLIN3) were not affected in COCs after treatment during IVM, although the expression of PTX3 (a cumulus cells expansion biomarker) was increased and the hatched blastocyst rate was increased by NPPC during IVM. During IVM, sildenafil increased the mRNA relative abundance of HSF1 and PAF1 and decreased REST in blastocysts. The use of sildenafil in IVC increased the LC of blastocysts. The mRNA abundance in blastocysts produced during IVC with sildenafil was changed for ATF4, XBP1, DNMT3A, DNMT3B, COX2, and SOX2. Although NPPC reduced the LC of oocytes after IVM and upregulated markers for cumulus expansion, embryo production was not affected and the produced blastocysts were able to regain their LC after IVC. Finally, the use of sildenafil during IVC increased the cytoplasmic LC of embryos but did not affect embryo quality, as measured by analysis of 96 transcripts related to embryo quality.


Asunto(s)
Células del Cúmulo/efectos de los fármacos , Ectogénesis/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Péptido Natriurético Tipo-C/farmacología , Oocitos/efectos de los fármacos , Citrato de Sildenafil/farmacología , Mataderos , Animales , Biomarcadores/metabolismo , Blastocisto/citología , Blastocisto/efectos de los fármacos , Blastocisto/metabolismo , Bovinos , Proliferación Celular/efectos de los fármacos , Células del Cúmulo/citología , Células del Cúmulo/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Técnicas de Cultivo de Embriones , Femenino , Fertilización In Vitro , Perfilación de la Expresión Génica , Técnicas de Maduración In Vitro de los Oocitos , Natriuréticos/metabolismo , Natriuréticos/farmacología , Péptido Natriurético Tipo-C/metabolismo , Oocitos/citología , Oocitos/metabolismo , Inhibidores de Fosfodiesterasa 5/farmacología , Técnicas de Cultivo de Tejidos
3.
Horm Mol Biol Clin Investig ; 31(2)2017 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-28949928

RESUMEN

ß-adrenergic receptors (ßARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the 'browning' of adipocytes within white fat depots (so-called 'brite' or 'beige' adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like ('beige' or 'brite') adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from ß-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.


Asunto(s)
Adipocitos Marrones/metabolismo , Sistemas de Mensajero Secundario , Transducción de Señal , Termogénesis , Adipocitos Beige/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Metabolismo Energético , Regulación de la Expresión Génica , Humanos , Espacio Intracelular/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , MicroARNs/genética , Natriuréticos/metabolismo , Natriuréticos/farmacología , ARN Largo no Codificante/genética , Receptores Adrenérgicos beta/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
4.
J Pharmacol Exp Ther ; 363(3): 358-366, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28928119

RESUMEN

8-Aminoguanosine induces diuresis, natriuresis, glucosuria, and antikaliuresis. These effects could be mediated via 8-aminoguanosine's metabolism to 8-aminoguanine. In this study, we tested this hypothesis in anesthetized rats. First, we demonstrated that at 55- to 85-minutes post-i.v. administration, 8-aminoguanosine and 8-aminoguanine (33.5 µmol/kg) significantly increased urine volume [ml/30 min: 8-aminoguanosine from 0.3 ± 0.1 to 0.9 ± 0.1 (mean ± S.E.M.; n = 7); 8-aminoguanine from 0.3 ± 0.1 to 1.5 ± 0.2 (n = 8)], sodium excretion (µmol/30 min: 8-aminoguanosine from 12 ± 5 to 109 ± 21; 8-aminoguanine from 18 ± 8 to 216 ± 31), and glucose excretion (µg/30 min: 8-aminoguanosine from 18 ± 3 to 159 ± 41; 8-aminoguanine from 17 ± 3 to 298 ± 65). Both compounds significantly decreased potassium excretion (µmol/30 min: 8-aminoguanosine from 62 ± 7 to 39 ± 9; 8-aminoguanine from 61 ± 10 to 34 ± 6). Next, we administered 8-aminoguanosine and 8-aminoguanine i.v. (33.5 µmol/kg) and measured renal interstitial (microdialysis probes) 8-aminoguanosine and 8-aminoguanine. The i.v. administration of 8-aminoguanosine and 8-aminoguanine similarly increased renal medullary interstitial levels of 8-aminoguanine [nanograms per milliliter; 8-aminoguanosine from 4 ± 1 to 1025 ± 393 (n = 6), and 8-aminoguanine from 2 ± 1 to 1069 ± 407 (n = 6)]. Finally, we determine the diuretic, natriuretic, glucosuric, and antikaliuretic effects of intrarenal artery infusions of 8-aminoguanosine and 8-aminoguanine (0.1, 0.3, and 1 µmol/kg/min). 8-Aminoguanine increased urine volume and sodium and glucose excretion by the ipsilateral kidney, yet had only mild effects at the highest dose in the contralateral kidney. Intrarenal infusions of 8-aminoguanosine did not induce diuresis, natriuresis, or glucosuria in either the ipsilateral or contralateral kidney, yet decreased potassium excretion in the ipsilateral kidney. Together these data confirm that the diuretic, natriuretic, and glucosuric effects of 8-aminoguanosine are not direct, but require metabolism to 8-aminoguanine. However, 8-aminoguanosine has direct antikaliuretic effects.


Asunto(s)
Diuréticos/farmacología , Glucosuria/orina , Guanina/análogos & derivados , Guanosina/análogos & derivados , Hiperpotasemia/tratamiento farmacológico , Natriuréticos/farmacología , Animales , Diuréticos/metabolismo , Guanina/metabolismo , Guanina/farmacología , Guanosina/metabolismo , Guanosina/farmacología , Guanosina/uso terapéutico , Hiperpotasemia/metabolismo , Médula Renal/efectos de los fármacos , Médula Renal/metabolismo , Masculino , Natriuréticos/metabolismo , Ratas Sprague-Dawley , Urodinámica/efectos de los fármacos
5.
Am J Physiol Renal Physiol ; 313(2): F378-F387, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28490529

RESUMEN

Sodium nitrite (NaNO2) is converted to nitric oxide (NO) in vivo and has vasodilatory and natriuretic effects. Our aim was to examine the effects of NaNO2 on hemodynamics, sodium excretion, and glomerular filtration rate (GFR). In a single-blinded, placebo-controlled, crossover study, we infused placebo (0.9% NaCl) or 0.58, 1.74, or 3.48 µmol NaNO2·kg-1·h-1 for 2 h in 12 healthy subjects, after 4 days of a standard diet. Subjects were supine and water loaded. We measured brachial and central blood pressure (BP), plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin (P-AVP), and plasma nitrite (P-[Formula: see text]), GFR by Cr-EDTA clearance, fractional excretion of sodium (FENa) free water clearance (CH2O), and urinary excretion rate of guanosine 3',5'-cyclic monophosphate (U-cGMP). The highest dose reduced brachial systolic BP (5.6 mmHg, P = 0.003), central systolic BP (5.6 mmHg, P = 0.035), and CH2O (maximum change from 3.79 to 1.27 ml/min, P = 0.031) and increased P-[Formula: see text] (from 0.065 to 0.766 µmol/l, P < 0.001), while reducing U-cGMP (from 444 to 247 pmol/min, P = 0.004). GFR, FENa, P-AVP, and the components in the renin-angiotensin-aldosterone system did not change significantly. In conclusion, intravenous NaNO2 induced a dose-dependent reduction of brachial and central BP. The hemodynamic effect was not mediated by the renin-angiotensin-aldosterone system. NaNO2 infusion resulted in a vasopressin-independent decrease in CH2O and urine output but no change in urinary sodium excretion or GFR. The lack of increase in cGMP accompanying the increase in [Formula: see text] suggests a direct effect of nitrite or nitrate on the renal tubules and vascular bed with little or no systemic conversion to NO.


Asunto(s)
Presión Arterial/efectos de los fármacos , Arteria Braquial/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/efectos de los fármacos , Natriuresis/efectos de los fármacos , Natriuréticos/administración & dosificación , Donantes de Óxido Nítrico/administración & dosificación , Nitrito de Sodio/administración & dosificación , Micción/efectos de los fármacos , Vasodilatadores/administración & dosificación , Adulto , Acuaporina 2/metabolismo , Biomarcadores/sangre , Estudios Cruzados , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Canales Epiteliales de Sodio/metabolismo , Femenino , Voluntarios Sanos , Humanos , Riñón/metabolismo , Masculino , Natriuréticos/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/metabolismo , Nitritos/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Método Simple Ciego , Nitrito de Sodio/metabolismo , Factores de Tiempo , Urodinámica/efectos de los fármacos , Vasodilatadores/metabolismo , Adulto Joven
6.
Life Sci ; 89(13-14): 460-6, 2011 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-21820448

RESUMEN

AIMS: C-type natriuretic peptide (CNP) is a local regulator of vascular tone and remodeling in many vascular beds. However, the role of CNP in modulating pulmonary arterial hypertensive and vascular remodeling responses is unclear. The purpose of this study was to determine if CNP is capable of preventing the development of pulmonary hypertension (PH). MAIN METHODS: We used animal models of PH caused by chronic hypoxia alone or in combination with the vascular endothelial growth factor (VEGF) receptor blocker SU5416. We measured pulmonary hemodynamics, right ventricular hypertrophy and vascular remodeling effects in response to a continuous infusion of low dose or high dose CNP or vehicle placebo. KEY FINDINGS: Right ventricular hypertrophy and a marked elevation in right ventricular systolic pressure (RVSP) were seen in both models of PH. Rats treated with the combination of SU5416 and chronic hypoxia also developed pulmonary endothelial hyperproliferative lesions. Continuous intravenous infusion of CNP at either dose did not attenuate the development of PH, right ventricular hypertrophy or vascular remodeling in either of the models of PH despite a three-fold increase in serum CNP levels. SIGNIFICANCE: CNP does not prevent the development of PH in the chronic hypoxia or SU5416 plus hypoxia models of pulmonary hypertension suggesting that CNP may not play an important modulatory role in human PH.


Asunto(s)
Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/prevención & control , Natriuréticos/metabolismo , Natriuréticos/uso terapéutico , Péptido Natriurético Tipo-C/metabolismo , Péptido Natriurético Tipo-C/uso terapéutico , Animales , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/complicaciones , Indoles/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Pirroles/efectos adversos , Ratas , Ratas Sprague-Dawley , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
7.
Am J Physiol Renal Physiol ; 301(2): F355-63, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21593184

RESUMEN

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 µg·kg(-1)·min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.


Asunto(s)
Péptido 1 Similar al Glucagón/metabolismo , Riñón/metabolismo , Natriuréticos/administración & dosificación , Animales , AMP Cíclico/orina , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Exenatida , Péptido 1 Similar al Glucagón/administración & dosificación , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes/farmacología , Riñón/efectos de los fármacos , Natriuréticos/metabolismo , Ácidos Pentanoicos/farmacología , Péptidos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Glucagón/metabolismo , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Tiazolidinas/farmacología , Ponzoñas
8.
Neurosurg Clin N Am ; 21(2): 339-52, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20380974

RESUMEN

Cerebral salt wasting (CSW) is a syndrome of hypovolemic hyponatremia caused by natriuresis and diuresis. The mechanisms underlying CSW have not been precisely delineated, although existing evidence strongly implicates abnormal elevations in circulating natriuretic peptides. The key in diagnosis of CSW lies in distinguishing it from the more common syndrome of inappropriate secretion of antidiuretic hormone. Volume status, but not serum and urine electrolytes and osmolality, is crucial for making this distinction. Volume and sodium repletion are the goals of treatment of patients with CSW, and this can be performed using some combination of isotonic saline, hypertonic saline, and mineralocorticoids.


Asunto(s)
Encefalopatías/complicaciones , Hiponatremia/diagnóstico , Hiponatremia/fisiopatología , Natriuréticos/metabolismo , Sodio/orina , Equilibrio Hidroelectrolítico/fisiología , Enfermedad Crítica/terapia , Diagnóstico Diferencial , Humanos , Hiponatremia/terapia , Hipovolemia/complicaciones , Hipovolemia/fisiopatología , Riñón/fisiopatología , Péptidos Natriuréticos/metabolismo , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiopatología
9.
Curr Mol Med ; 9(7): 814-25, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19860661

RESUMEN

B-type natriuretic peptide (BNP), initially identified in brain tissues, is now recognized as a key cardiac hormone. Numerous studies over the last decade have demonstrated that both exogenous and endogenous BNP prevent left ventricular (LV) hypertrophy in experimental settings, largely via activation of particulate guanylyl cyclase (pGC)-coupled receptors. BNP represents somewhat of a paradox, in that upregulation of BNP expression is widely used as a diagnostic marker for LV hypertrophy, diastolic dysfunction and heart failure in the clinic. We and others have postulated that BNP serves as an endogenous brake on the LV myocardium, seeking to curb the runaway train of signaling pathways that drive the progression from LV hypertrophy though remodeling, heart failure and death. This review summarizes the mechanisms of BNP's antihypertrophic actions, the role for cyclic GMP-mediated inhibition of pro-hypertrophic signaling, and BNP's impact on LV function. The improved understanding of the mechanisms of BNP regulation of LV hypertrophy and function that has emerged from both the experimental and clinical experience with this peptide provides new insight into the potential that BNP pharmacotherapy still offers for patients with LV hypertrophy.


Asunto(s)
Biomarcadores/metabolismo , Miocardio/metabolismo , Péptido Natriurético Encefálico/metabolismo , Isoformas de Proteínas/metabolismo , Animales , Antioxidantes/metabolismo , Cardiotónicos/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Humanos , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/patología , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Miocardio/citología , Miocardio/patología , Natriuréticos/metabolismo , Biosíntesis de Proteínas , Receptores del Factor Natriurético Atrial/metabolismo , Transducción de Señal/fisiología , Transcripción Genética , Función Ventricular Izquierda/fisiología , Remodelación Ventricular
10.
Orv Hetil ; 150(30): 1397-402, 2009 Jul 26.
Artículo en Húngaro | MEDLINE | ID: mdl-19592334

RESUMEN

Congestive heart failure is a chronic disease, whose incidence is especially growing in the subpopulation of elderly people. The majority of these patients have vitamin D levels in the insufficient range. Skin synthesis is the most important vitamin D source for humans. Congestive heart failure patients have relatively low outdoor activities. Consequently, a disease-related sedentary lifestyle is an important cause for the insufficient vitamin D status in patients. However, there is an accumulating body of evidence that vitamin D insufficiency plays a role in the etiology and pathogenesis of congestive heart failure. Vitamin D has direct effect on heart cells and indirect effect on the risk factors of the disease. Four major potential mechanisms may be important to explain the direct effects of vitamin D against congestive heart failure: the effect on myocardial contractile function, the regulation of natriuretic hormone secretion, the effect on extracellular matrix remodelling and the regulation of inflammation cytokines. It has been demonstrated that vitamin D has a high impact on congestive heart failure main risk factors as hypertension, renin-angiotensin system malfunction and atherosclerosis. In spite of the robust preclinical data only few clinical observations prove the positive effect of vitamin D on congestive heart failure.


Asunto(s)
Insuficiencia Cardíaca/etiología , Deficiencia de Vitamina D/complicaciones , Envejecimiento , Animales , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Estilo de Vida , Contracción Miocárdica , Natriuréticos/metabolismo , Factores de Riesgo , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/etiología , Deficiencia de Vitamina D/metabolismo , Deficiencia de Vitamina D/fisiopatología
12.
Respir Med ; 103(2): 180-6, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19097877

RESUMEN

BACKGROUND: Pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is associated with poor prognosis. Recently echocardiography and brain natriuretic peptide (BNP) have been used as non-invasive markers for PH suggesting that they may also be used as markers for survival. The aim of this study was to evaluate the clinical usefulness of echocardiography and BNP by analyzing their association with survival. METHODS: Retrospective review of 131 patients with IPF who underwent both echocardiography and BNP measurement at a tertiary referral center. RESULTS: Mean follow-up period was 10.1 months. Using systolic pulmonary arterial pressure of 40 mmHg as a threshold for PH, patients with PH had poor survival (1-year mortality rate: 61.2%, mean survival: 10.8 months) than those without PH (19.9%, 23.7 months; p<0.001). The prognosis of the subjects with increased BNP levels was poorer than those with normal BNP levels (1-year mortality rate: 70.5% vs. 23.7%, mean survival: 11.0 months vs. 22.5 months; p<0.001) and on multivariate analysis, only BNP level was an independent predictor of prognosis. On serial evaluation, the survival of patients with newly developed PH and/or elevated BNP levels was similar to that of patients with PH at the initial measurement, suggesting that development of PH is indicative of poor prognosis regardless of the timing of the test. CONCLUSIONS: Although both BNP level and PH by echocardiography are clinically useful non-invasive and easily repeatable markers of prognosis, BNP level seems to be better.


Asunto(s)
Hipertensión Pulmonar/diagnóstico , Fibrosis Pulmonar Idiopática/diagnóstico , Natriuréticos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Anciano , Biomarcadores/metabolismo , Ecocardiografía/métodos , Femenino , Hemodinámica/fisiología , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Fibrosis Pulmonar Idiopática/mortalidad , Fibrosis Pulmonar Idiopática/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
13.
Endocrinology ; 149(9): 4486-98, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18499760

RESUMEN

Orally delivered salt stimulates renal salt excretion more effectively than does iv delivered salt. Although the mechanisms that underlie this "postprandial natriuresis" are poorly understood, the peptide uroguanylin (UGn) is thought to be a key mediator. However, the lack of selective assays for UGn gene products has hindered rigorous testing of this hypothesis. Using peptide-specific assays, we now report surprisingly little UGn in rat intestine or plasma. In contrast, prouroguanylin (proUGn), the presumed-inactive precursor of UGn, is plentiful (at least 40 times more abundant than UGn) in both intestine and plasma. The intestine is the likely source of the circulating proUGn because: 1) the proUGn portal to systemic ratio is approximately two under normal conditions, and 2) systemic proUGn levels decrease rapidly after intestinal resection. Together, these data suggest that proUGn itself is actively involved in enterorenal signaling. This is strongly supported by our observation that iv infusion of proUGn at a physiological concentration produces a long-lasting renal natriuresis, whereas previously reported natriuretic effects of UGn have required supraphysiological concentrations. Thus, our data point to proUGn as an endocrine (i.e. circulating) mediator of postprandial natriuresis, and suggest that the propeptide is secreted intact from the intestine into the circulation and processed to an active form at an extravascular site.


Asunto(s)
Riñón/metabolismo , Péptidos Natriuréticos/metabolismo , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Hormonas Gastrointestinales/sangre , Hormonas Gastrointestinales/metabolismo , Intestinos/química , Masculino , Natriuréticos/sangre , Natriuréticos/metabolismo , Péptidos Natriuréticos/sangre , Precursores de Proteínas/sangre , Precursores de Proteínas/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Sodio/metabolismo , Extractos de Tejidos/química
14.
Endocrinology ; 149(9): 4499-509, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18499761

RESUMEN

The intestine and kidney are linked by a mechanism that increases salt excretion in response to salt intake. The peptide uroguanylin (UGn) is thought to mediate this signaling axis. Therefore, it was surprising to find (as reported in a companion publication) that UGn is stored in the intestine and circulates in the plasma almost exclusively in the form of its biologically inactive propeptide precursor, prouroguanylin (proUGn), and, furthermore, that infused proUGn leads to natriuretic activity. Here, we investigate the fate of circulating proUGn. Kinetic studies show rapid renal clearance of radiolabeled propeptide. Radiolabel accumulates at high specific activity in kidney (relative to other organs) and urine (relative to plasma). The principal metabolites found in kidney homogenates are free cysteine and methionine. In contrast, urine contains cysteine, methionine, and three other radioactive peaks, one comigrating with authentic rat UGn15. Interestingly, proUGn is not converted to these or other metabolites in plasma, indicating that circulating proUGn is not processed before entering the kidney. Therefore, our findings suggest that proUGn is the true endocrine agent released in response to salt intake and that the response of the kidney is dependent on conversion of the propeptide to an active form after it reaches the renal tubules. Furthermore, proUGn metabolites (other than small amounts of cysteine and methionine) are not returned to the circulation from the kidney or any other organ. Thus, to respond to proUGn released from the gut, any target organ must use a local mechanism for production of active peptide.


Asunto(s)
Túbulos Renales/metabolismo , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Secuencia de Aminoácidos , Animales , Endotelio Vascular/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Datos de Secuencia Molecular , Natriuréticos/metabolismo , Precursores de Proteínas/sangre , Precursores de Proteínas/farmacocinética , Precursores de Proteínas/orina , Ratas , Ratas Wistar , Radioisótopos de Azufre/farmacocinética
16.
Life Sci ; 80(23): 2093-2107, 2007 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-17499813

RESUMEN

Digitalis-like compounds (DLC) are a family of steroid hormones synthesized in and released from the adrenal gland. DLC, the structure of which resembles that of plant cardiac glycosides, bind to and inhibit the activity of the ubiquitous cell surface enzyme Na(+), K(+)-ATPase. However, there is a large body of evidence suggesting that the regulation of ion transport by Na(+), K(+)-ATPase is not the only physiological role of DLC. The binding of DLC to Na(+), K(+)-ATPase induces the activation of various signal transduction cascades that activate changes in intracellular Ca(++) homeostasis, and in specific gene expression. These, in turn, stimulate endocytosis and affect cell growth and proliferation. At the systemic level, DLC were shown to be involved in the regulation of major physiological parameters including water and salt homeostasis, cardiac contractility and rhythm, systemic blood pressure and behavior. Furthermore, the DLC system has been implicated in several pathological conditions, including cardiac arrhythmias, hypertension, cancer and depressive disorders. This review evaluates the evidence for the different aspects of DLC action and delineates open questions in the field.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Digitalis/metabolismo , Potasio/química , Sodio/metabolismo , Esteroides/metabolismo , Animales , Transporte Biológico , Endocitosis , Humanos , Iones , Modelos Biológicos , Natriuréticos/metabolismo , Ouabaína/farmacología , Extractos Vegetales/farmacología , ATPasa Intercambiadora de Sodio-Potasio/química
17.
Pediatr Crit Care Med ; 7(4): 308-18, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16760825

RESUMEN

OBJECTIVE: To review the natriuretic hormone system and discuss its diagnostic, prognostic, and therapeutic potential in critically ill children. DATA SOURCE: A thorough literature search of MEDLINE was performed using search terms including heart defects, congenital; cardiopulmonary bypass, atrial natriuretic factor; natriuretic peptide, brain; carperitide; nesiritide. Preclinical and clinical investigations and review articles were identified that describe the current understanding of the natriuretic hormone system and its role in the regulation of vascular tone and fluid balance in healthy adults and children and in those with underlying cardiac, pulmonary, and renal disease. RESULTS: A predictable activation of the natriuretic hormone system occurs in children with congenital heart disease and congestive heart failure. Further study is needed to confirm preliminary reports that measurement of natriuretic hormone levels in critically ill children provides diagnostic and prognostic information, as has been demonstrated in adult cardiac populations. Natriuretic hormone infusions provide favorable hemodynamic changes and symptomatic relief when used in adults with decompensated congestive heart failure, and uncontrolled case series suggest that similar benefits may exist in children. The biological activity of the natriuretic hormone system may be decreased following pediatric cardiopulmonary bypass, and additional studies are needed to determine whether natriuretic hormone infusions provide clinical benefit in the postoperative period. Preliminary reports suggest that natriuretic hormone infusions cause physiologic improvements in adults with acute lung injury and asthma but not in those with acute renal failure. CONCLUSIONS: Although important perturbations of the natriuretic hormone system occur in critically ill infants and children, further investigation is needed before the measurement of natriuretic peptides and the use of natriuretic hormone infusions are incorporated into routine practice.


Asunto(s)
Factor Natriurético Atrial , Cuidados Críticos , Natriuréticos , Péptido Natriurético Encefálico , Adolescente , Factor Natriurético Atrial/metabolismo , Factor Natriurético Atrial/farmacología , Factor Natriurético Atrial/fisiología , Factor Natriurético Atrial/uso terapéutico , Biomarcadores/metabolismo , Puente Cardiopulmonar , Niño , Preescolar , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/tratamiento farmacológico , Cardiopatías Congénitas/cirugía , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/cirugía , Humanos , Lactante , Recién Nacido , Natriuréticos/metabolismo , Natriuréticos/farmacología , Natriuréticos/fisiología , Natriuréticos/uso terapéutico , Péptido Natriurético Encefálico/metabolismo , Péptido Natriurético Encefálico/farmacología , Péptido Natriurético Encefálico/fisiología , Péptido Natriurético Encefálico/uso terapéutico
18.
Regul Pept ; 133(1-3): 13-9, 2006 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-16289365

RESUMEN

The present study used isolated rat hearts to investigate whether (1) Dendroaspis natriuretic peptide (DNP) is protective against post-ischemic myocardial dysfunction, and (2) whether the cardioprotective effects of DNP is related to alteration of Bcl-2 family protein levels. The excised hearts of Sprague-Dawley rats were perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. Left ventricular end-diastolic pressure (LVEDP, mmHg), left ventricular developed pressure (LVDP, mmHg) and coronary flow (CF, ml/min) were continuously monitored. In the presence of 50 nM DNP, all hearts were perfused for a total of 100 min consisting of a 20 min pre-ischemic period followed by a 30 min global ischemia and 50 min reperfusion. Lactate dehydrogenase (LDH) activity in the effluent was measured during reperfusion. Treatment with DNP alone improved the pre-ischemic LVEDP and post-ischemic LVEDP significantly comparing with the untreated control hearts during reperfusion. However, DNP did not affect the LVDP, heart rate (HR, beats/min), and CF. Bcl-2, an anti-apoptotic protein expressed in ischemic myocardium of DNP+ischemia/reperfusion (I/R) group, was higher than that in I/R alone group. Bax, a pro-apoptotic protein expressed in ischemic myocardium of DNP+I/R group, has no significant difference compared with I/R alone group. These results suggest that the protective effects of DNP against I/R injury would be mediated, at least in part, through the increased ratio of Bcl-2 to Bax protein after ischemia-reperfusion.


Asunto(s)
Venenos Elapídicos/farmacología , Genes bcl-2 , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Péptidos/farmacología , Animales , Apoptosis , Venenos Elapídicos/metabolismo , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , L-Lactato Deshidrogenasa/metabolismo , Microscopía Fluorescente , Isquemia Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Natriuréticos/metabolismo , Natriuréticos/farmacología , Natriuréticos/uso terapéutico , Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína X Asociada a bcl-2/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo
19.
Front Biosci ; 10: 2325-34, 2005 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15970498

RESUMEN

The sodium pump is a ubiquitous cell surface enzyme, a Na/K-ATPase, that maintains ion gradients between cells and the extracellular fluid. The extracellular domain of this enzyme contains a highly conserved receptor for a plant-derived family of compounds, the digitalis glycosides, used in the treatment of congestive heart failure, and certain cardiac arrhythmias. The concept that an endogenous modulator of this enzyme, analogous to the cardiac glycosides, emerged from work on two separate areas: the regulation of extracellular fluid (ECF) volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na/K-ATPase. These two areas merged with the hypothesis that natriuretic hormone and the vascular Na/K-ATPase inhibitor were the same factor, and furthermore, that this factor played a causative role in the pathophysiology of certain types of hypertension. In this communication, the development of this field from its beginnings is traced; evidence for the existence of and efforts to identify the structure of this factor are briefly reviewed, and suggestions for future development of the field are put forward.


Asunto(s)
Cardenólidos/metabolismo , Glicósidos Digitálicos/metabolismo , Saponinas/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Cardenólidos/historia , Digoxina/inmunología , Historia del Siglo XXI , Humanos , Hipertensión/metabolismo , Natriuréticos/metabolismo , Ouabaína/metabolismo , Saponinas/historia
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