RESUMEN
The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.
Asunto(s)
Furosemida , Insuficiencia Cardíaca , Riñón , Péptido Natriurético Encefálico , Sodio , Volumen Sistólico , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Masculino , Femenino , Anciano , Proyectos Piloto , Furosemida/farmacología , Furosemida/administración & dosificación , Sodio/metabolismo , Sodio/orina , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/metabolismo , Riñón/metabolismo , Riñón/fisiopatología , Riñón/efectos de los fármacos , Persona de Mediana Edad , Natriuresis/efectos de los fármacos , Diuréticos/farmacología , Diuréticos/administración & dosificación , GMP Cíclico/metabolismo , GMP Cíclico/orina , Anciano de 80 o más AñosRESUMEN
Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.
Asunto(s)
Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Péptido Natriurético Encefálico/uso terapéutico , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Tadalafilo/uso terapéutico , Anciano , Anciano de 80 o más Años , GMP Cíclico/sangre , GMP Cíclico/orina , Combinación de Medicamentos , Femenino , Tasa de Filtración Glomerular , Insuficiencia Cardíaca Diastólica/fisiopatología , Humanos , Masculino , Contracción Miocárdica , Péptido Natriurético Encefálico/administración & dosificación , Péptido Natriurético Encefálico/efectos adversos , Péptido Natriurético Encefálico/farmacocinética , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Inhibidores de Fosfodiesterasa 5/efectos adversos , Inhibidores de Fosfodiesterasa 5/farmacocinética , Eliminación Renal , Tadalafilo/administración & dosificación , Tadalafilo/efectos adversos , Tadalafilo/farmacocinéticaRESUMEN
PURPOSE: To characterize the safety, pharmacodynamics, and pharmacokinetics (PK) of vericiguat in healthy males. METHODS: Six phase I studies were conducted in European, Chinese, and Japanese males. Subjects received oral vericiguat as a single dose (0.5-15.0 mg solution [for first-in-human study] or 1.25-10.0 mg immediate release [IR tablets]) or multiple doses (1.25-10.0 mg IR tablets once daily [QD] or 5.0 mg IR tablets twice daily for 7 consecutive days). Bioavailability and food effects on vericiguat PK (IR tablets) were also studied in European subjects. RESULTS: Overall, 255 of 265 randomized subjects completed their respective studies. There were no deaths or serious adverse events. Vericiguat was generally well tolerated at doses ≤ 10.0 mg. In the first-in-human study, the most frequent drug-related adverse events were headache and postural dizziness (experienced by five subjects each [7.2%]). Three of four subjects who received vericiguat 15.0 mg (oral solution, fasted) experienced orthostatic reactions. Vericiguat (≤ 10.0 mg, IR tablets) was rapidly absorbed (median time to reach maximum plasma concentration ≤ 2.5 h [fasted]) with a mean half-life of about 22.0 h (range 17.9-27.0 h for single and multiple doses). No evidence for deviation from dose proportionality or unexpected accumulation was observed. Administration of vericiguat 5.0 mg IR tablets with food increased bioavailability by 19% (estimated ratio 119% [90% confidence interval]: 108; 131]), reduced PK variability, and prolonged vericiguat absorption relative to the fasted state. CONCLUSION: In general, vericiguat was well tolerated. These results supported further clinical evaluation of vericiguat QD in patients with heart failure. REGISTRY NUMBERS: EudraCT: 2011-001627-21; EudraCT: 2012-000953-30.
Asunto(s)
Compuestos Heterocíclicos con 2 Anillos , Pirimidinas , Guanilil Ciclasa Soluble , Administración Oral , Adulto , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , GMP Cíclico/sangre , GMP Cíclico/orina , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Preparaciones de Acción Retardada/farmacocinética , Método Doble Ciego , Esquema de Medicación , Epinefrina/sangre , Interacciones Alimento-Droga , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Compuestos Heterocíclicos con 2 Anillos/sangre , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Masculino , Norepinefrina/sangre , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/sangre , Pirimidinas/farmacocinética , Método Simple Ciego , Resistencia Vascular/efectos de los fármacosRESUMEN
BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
Asunto(s)
Acondroplasia/tratamiento farmacológico , Crecimiento/efectos de los fármacos , Péptido Natriurético Tipo-C/análogos & derivados , Osteogénesis/efectos de los fármacos , Acondroplasia/fisiopatología , Adolescente , Biomarcadores/análisis , Estatura/efectos de los fármacos , Niño , Preescolar , Colágeno/sangre , GMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Femenino , Gráficos de Crecimiento , Humanos , Inyecciones Subcutáneas , Masculino , Péptido Natriurético Tipo-C/administración & dosificación , Péptido Natriurético Tipo-C/efectos adversos , Péptido Natriurético Tipo-C/uso terapéuticoRESUMEN
We have recently reported that type A intercalated cells of the collecting duct secrete Na+ by a mechanism coupling the basolateral type 1 Na+-K+-2Cl- cotransporter with apical type 2 H+-K+-ATPase (HKA2) functioning under its Na+/K+ exchange mode. The first aim of the present study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with Na+ retention. The second aim of the present study was to evaluate whether ANP-induced stimulation of Na+ secretion by type A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increased the membrane expression, activity, and Na+-transporting rate of HKA2. Feeding mice with a NH4Cl-enriched diet increased urinary excretion of aldosterone and induced a transient Na+ retention that reversed within 3 days. At that time, expression of ANP mRNA in the collecting duct and urinary excretion of cGMP were increased. Reversion of Na+ retention was prevented by treatment with an inhibitor of ANP receptors and was absent in HKA2-null mice. In conclusion, paracrine stimulation of HKA2 by ANP is responsible for the escape of the Na+-retaining effect of aldosterone during metabolic acidosis.
Asunto(s)
Equilibrio Ácido-Base , Acidosis/enzimología , Factor Natriurético Atrial/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Túbulos Renales Colectores/enzimología , Sodio/orina , Acidosis/genética , Acidosis/fisiopatología , Acidosis/orina , Adaptación Fisiológica , Aldosterona/orina , Animales , GMP Cíclico/orina , Femenino , ATPasa Intercambiadora de Hidrógeno-Potásio/deficiencia , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Concentración de Iones de Hidrógeno , Ratones Endogámicos C57BL , Ratones Noqueados , Comunicación Paracrina , Ratas , Transducción de Señal , Xenopus laevisRESUMEN
AIMS: Circulating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3'5' monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF). METHODS AND RESULTS: PIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome. CONCLUSION: Biomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1-4 weeks. CLINICAL TRIALS REGISTRATION: NCT02554890 clinical.trials.gov.
Asunto(s)
Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Enalapril/uso terapéutico , Insuficiencia Cardíaca , Tetrazoles/uso terapéutico , Anciano , Biomarcadores/sangre , Compuestos de Bifenilo , GMP Cíclico/orina , Combinación de Medicamentos , Femenino , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Hemodinámica , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Troponina/sangre , ValsartánRESUMEN
OBJECTIVES: The combination of AT1 blocker/neutroendopeptidase neprilysin inhibition (ARNi) represents an interesting approach to reduce cardiovascular risk in hypertension. We assessed the efficacy of ARNi, compared with angiotensin II type 1 receptor blockade alone, on blood pressure (BP) and on protection from target organ damage development in the stroke-prone spontaneously hypertensive rat (SHRSP). METHODS: In high-salt fed SHRSP, we assessed plasma and tissue natriuretic peptides, urinary volume, BP and body weight over a short-term treatment (6 weeks) with either ARNi (sacubitril/valsartan 68âmg/kg per day) or valsartan (30âmg/kg per day), protection from stroke and renal damage (as documented by proteinuria) over 4 months of treatment with either sacubitril/valsartan or valsartan; the ability of either treatment to reduce progression of cerebrovascular and renal damage after 2 weeks of high-salt diet. RESULTS: Higher levels of plasma and tissue atrial natriuretic peptide, of urinary cyclic guanosine 3'5'monophosphate and urine volumes, along with lower BP levels, were found upon sacubitril/valsartan as compared with valsartan over the short-term treatment. Sacubitril/valsartan caused a significant reduction of both BP and proteinuria levels and complete prevention of stroke over the long-term treatment. Once organ damage was established, a significant delay of its progression was observed with sacubitril/valsartan. CONCLUSION: The dual angiotensin II type 1 receptor/neutroendopeptidase inhibition significantly increased atrial natriuretic peptide level and reduced BP. Complete prevention of stroke was achieved in this model. The ability of sacubitril/valsartan to reduce organ damage progression was superior to that of valsartan alone. ARNi may represent a highly effective therapeutic agent to protect from target organ damage development in hypertension.
Asunto(s)
Aminobutiratos/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Tetrazoles/uso terapéutico , Valsartán/uso terapéutico , Animales , Factor Natriurético Atrial/metabolismo , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/orina , Combinación de Medicamentos , Masculino , Neprilisina/antagonistas & inhibidores , Proteinuria/tratamiento farmacológico , Ratas , Ratas Endogámicas SHRRESUMEN
BACKGROUND: The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in-hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography. METHODS: Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charité Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE. RESULTS: In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean±SD was predictive for the need of dialysis (no dialysis: 89.77±92.85 µM/mM, n = 277; need for dialysis: 140.3±82.90 µM/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60±92.50 µM/mM, n = 280; death during follow-up: 169.88±81.52 µM/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02±93.17 µM/mM, n = 271; MARE: 146.64±74.68 µM/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 µM/mM in patients who developed MARE, required dialysis or died. CONCLUSIONS: Urinary cGMP/creatinine ratio ≥ 120 µM/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes.
Asunto(s)
Medios de Contraste/efectos adversos , GMP Cíclico/orina , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/orina , Enfermedades Renales/etiología , Enfermedades Renales/orina , Anciano , Biomarcadores , Estudios de Cohortes , Creatinina/orina , Nefropatías Diabéticas/diagnóstico por imagen , Femenino , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/diagnóstico , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Factores de TiempoRESUMEN
Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.
Asunto(s)
Aminobutiratos/farmacología , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/farmacocinética , Antihipertensivos/farmacología , Antihipertensivos/farmacocinética , Hipertensión/tratamiento farmacológico , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/farmacocinética , Tetrazoles/farmacología , Tetrazoles/farmacocinética , Aminobutiratos/efectos adversos , Antagonistas de Receptores de Angiotensina/efectos adversos , Antihipertensivos/efectos adversos , Factor Natriurético Atrial/orina , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/orina , Método Doble Ciego , Combinación de Medicamentos , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Citrato de Sildenafil/efectos adversos , Tetrazoles/efectos adversos , ValsartánRESUMEN
BACKGROUND: We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model. METHODS: C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC. The L-NAME-treated dams were divided into 2 subgroups 13 d.p.c. One subgroup continued to receive L-NAME (L dams). The other subgroup received L-NAME with 0.08 mg/ml tadalafil suspended in CMC (TL dams). Maternal systolic blood pressure (SBP) and proteinuria were assessed 16 d.p.c. Fetal weight was recorded, and placentas and maternal kidneys were collected 17 d.p.c. RESULTS: Maternal SBP, proteinuria, and fetal weight were improved for TL dams compared to L dams. The placental concentration of placental growth factor (PlGF) was higher for TL dams than for the C and L dams. The placental maternal blood sinuses of L dams were narrower than those of C dams, but those of TL dams improved to a similar width as C dams. Glomerular oxidative stress was ameliorated in TL dams compared to L dams. CONCLUSIONS: Tadalafil dilates the placental maternal blood sinuses, which leads to increase PlGF production, and contributes to facilitate fetal growth and improve maternal SBP. Moreover, tadalafil ameliorates glomerular damage by reducing oxidative stress. These results suggest that tadalafil is a candidate for treatment of PE with FGR.
Asunto(s)
Inhibidores Enzimáticos , Retardo del Crecimiento Fetal/inducido químicamente , Retardo del Crecimiento Fetal/prevención & control , NG-Nitroarginina Metil Éster , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Preeclampsia/inducido químicamente , Preeclampsia/prevención & control , Tadalafilo/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/orina , Femenino , Desarrollo Fetal/efectos de los fármacos , Retardo del Crecimiento Fetal/patología , Riñón/patología , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Placenta/patología , Preeclampsia/patología , Embarazo , Proteinuria/inducido químicamenteRESUMEN
AIMS: Cenderitide is a novel dual natriuretic peptide (NP) receptor chimeric peptide activator, which targets the particulate guanylyl cyclase B (pGC-B) receptor and pGC-A unlike native NPs. Cenderitide was engineered to retain the anti-fibrotic properties of C-type natriuretic peptide (CNP)/pGC-B with renal-enhancing actions facilitated by fusion to the carboxyl terminus of Dendroaspis NP (DNP), a pGC-A agonist, to CNP. Here, we address significance of the DNP carboxyl terminus in dual pGC receptor activation and actions of cenderitide compared with CNP on renal function and cyclic guanosine monophosphate (cGMP) in vivo and ex vivo in normal canines. METHODS AND RESULTS: In vitro, only cenderitide and not CNP or three CNP-based variants was a potent dual pGC-A/pGC-B activator of cGMP production (from 5 to 237 pmol/mL) in human embryonic kidney (HEK) 293 cells overexpressing human pGC-A while in pGC-B overexpressing cells cenderitide increased cGMP production (from 4 to 321 pmol/mL) while the three CNP-based variants were weak agonists. Based upon our finding that the DNP carboxyl terminus is a key structural requirement for dual pGC-A/pGC-B activation, we defined in vivo the renal-enhancing actions of cenderitide compared with CNP. Cenderitide increased urinary cGMP excretion (from 989 to 5977 pmol/mL), net generation of renal cGMP (821-4124 pmol/min), natriuresis (12-242 µEq/min), and glomerular filtration rate (GFR) (37-51 mL/min) while CNP did not. We then demonstrated the transformation of CNP ex vivo into a renal cGMP-activating peptide which increased cGMP in freshly isolated glomeruli eight-fold greater than CNP. CONCLUSION: The current study establishes that dual pGC-A and pGC-B activation with CNP requires the specific carboxyl terminus of DNP. In normal canines in vivo and in glomeruli ex vivo, the carboxyl terminus of DNP transforms CNP into a natriuretic and GFR-enhancing peptide. Future studies of cenderitide are warranted in cardiorenal disease states to explore its efficacy in overall cardiorenal homeostasis.
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Natriuréticos/farmacología , Péptidos Natriuréticos/farmacología , Receptores del Factor Natriurético Atrial/agonistas , Fármacos Renales/farmacología , Venenos de Serpiente/farmacología , Animales , GMP Cíclico/orina , Dendroaspis , Perros , Diseño de Fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Células HEK293 , Humanos , Pruebas de Función Renal , Masculino , Natriuréticos/química , Péptido Natriurético Tipo-C/química , Péptido Natriurético Tipo-C/farmacología , Péptidos Natriuréticos/química , Venenos de Serpiente/química , Relación Estructura-ActividadRESUMEN
OBJECTIVES: This study determined whether there is development of tachyphylaxis to enhancement of cardiorenal response to acute volume loading (AVL) with B-type natriuretic peptide (BNP) after 12-week, twice-daily subcutaneous BNP administration in patients with preclinical diastolic dysfunction (PDD). BACKGROUND: PDD is characterized by normal systolic function and moderate or severe diastolic dysfunction but no symptoms of heart failure (HF). Impairment in cardiorenal endocrine response to stress by AVL exists in PDD and is corrected by acute administration of subcutaneous BNP. METHODS: A double-blinded, placebo-controlled proof-of-concept study was conducted to compare 12 weeks of twice daily subcutaneous BNP, 10 µg/kg (n = 24), versus placebo (n = 12) in PDD. Subjects underwent 2 study visits, at baseline and after 12 weeks. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular AVL. RESULTS: Among those with PDD, there was a statistically significant improvement in diastolic function after 12 weeks of BNP, as measured by a decrease in the Doppler E/e' ratio (where E is early mitral inflow velocity and e' is mitral annulus early diastolic motion) (p = 0.004) and improvement of diastolic dysfunction grade (p = 0.008). After 12 weeks, there was statistically significantly greater sodium excretion, urine flow, and urinary cyclic guanosine monophosphate excretion to AVL (all p < 0.001), as well as a trend toward greater glomerular filtration rate (p = 0.050) in the BNP group as compared to the placebo group. CONCLUSIONS: In subjects with PDD, chronic BNP administration resulted in sustained improvement in diastolic function without development of tachyphylaxis to the enhancement of cardiorenal response to volume expansion with BNP. (Human Brain Natriuretic Peptide [BNP] [or Nesiritide] to Help Heart, Kidney and Humoral Function; NCT00405548).
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Enfermedades Asintomáticas , Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Natriuréticos/uso terapéutico , Péptido Natriurético Encefálico/uso terapéutico , Anciano , Anciano de 80 o más Años , Velocidad del Flujo Sanguíneo , GMP Cíclico/orina , Método Doble Ciego , Ecocardiografía , Femenino , Insuficiencia Cardíaca Diastólica/diagnóstico por imagen , Insuficiencia Cardíaca Diastólica/fisiopatología , Insuficiencia Cardíaca Diastólica/orina , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Válvula Mitral , Prueba de Estudio Conceptual , Sodio/orina , Taquifilaxis , Resultado del TratamientoRESUMEN
AIMS: We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. METHODS AND RESULTS: We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (-39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. CONCLUSION: Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.
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Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Natriuréticos/uso terapéutico , Péptido Natriurético Encefálico/uso terapéutico , Sodio/orina , Anciano , Enfermedades Asintomáticas , Factor Natriurético Atrial/metabolismo , GMP Cíclico/sangre , GMP Cíclico/orina , Método Doble Ciego , Ecocardiografía , Femenino , Fluidoterapia , Tasa de Filtración Glomerular , Insuficiencia Cardíaca Sistólica/diagnóstico por imagen , Insuficiencia Cardíaca Sistólica/metabolismo , Insuficiencia Cardíaca Sistólica/fisiopatología , Humanos , Infusiones Subcutáneas , Riñón/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, L-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-ß-D-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function.
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Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Ácidos Aristolóquicos , Óxido Nítrico/uso terapéutico , Lesión Renal Aguda/patología , Animales , Arginina/farmacología , Creatinina/sangre , GMP Cíclico/orina , Riñón/patología , Túbulos Renales Proximales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Poliuria/inducido químicamente , Poliuria/prevención & control , Proteinuria/inducido químicamente , Proteinuria/prevención & control , Sodio/orina , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and nonsteroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. PATIENT AND METHODS: A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. RESULTS: Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. CONCLUSIONS: Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy.
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Diabetes Insípida Nefrogénica/tratamiento farmacológico , Diabetes Insípida Nefrogénica/orina , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Acuaporina 2/orina , Preescolar , GMP Cíclico/orina , Humanos , Masculino , Concentración Osmolar , Sodio/sangre , Urinálisis , OrinaRESUMEN
Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). The loop diuretic furosemide is a potent inhibitor of NKCC2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well-established effects of nitric oxide on NKCC2 activity, cGMP is likely involved in this regulation. cGMP-dependent protein kinase I (cGKI; PKGI) is a cGMP target protein that phosphorylates different substrates after activation through cGMP. We investigated the potential correlation between the cGMP/cGKI pathway and NKCC2 regulation. We treated wild-type (wt) and cGKIα-rescue mice with furosemide. cGKIα-rescue mice expressed cGKIα only under the control of the smooth muscle-specific transgelin (SM22) promoter in a cGKI deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in cGKIα-rescue mice compared to that in wt mice. We analyzed the phosphorylation of NKCC2 by western blotting and immunostaining using the phosphospecific antibody R5. The administration of furosemide significantly increased the phosphorylated NKCC2 signal in wt but not in cGKIα-rescue mice. NKCC2 activation led to its phosphorylation and membrane translocation. To examine whether cGKI was involved in this process, we analyzed vasodilator-stimulated phosphoprotein, which is phosphorylated by cGKI. Furosemide injection resulted in increased vasodilator-stimulated phosphoprotein phosphorylation in wt mice. We hypothesize that furosemide administration activated cGKI, leading to NKCC2 phosphorylation and membrane translocation. This cGKI-mediated pathway could be a mechanism to compensate for the inhibitory effect of furosemide on NKCC2.
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Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Furosemida/farmacología , Riñón/metabolismo , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo , Animales , Moléculas de Adhesión Celular/metabolismo , GMP Cíclico/metabolismo , GMP Cíclico/orina , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/genética , Femenino , Riñón/efectos de los fármacos , Masculino , Ratones Noqueados , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Potasio/orina , Renina/sangre , Sodio/orina , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Miembro 1 de la Familia de Transportadores de Soluto 12/antagonistas & inhibidores , Miembro 1 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
OBJECTIVE: Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome. STUDY DESIGN: Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20-2 ppm. A control group of 19 infants did not receive iNO. RESULTS: In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10-20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses. CONCLUSION: Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO-cGMP pathway in lung development.
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Displasia Broncopulmonar/prevención & control , GMP Cíclico/orina , Enfermedades del Prematuro/prevención & control , Óxido Nítrico/orina , Administración por Inhalación , Biomarcadores/orina , Creatinina/orina , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Óxido Nítrico/administración & dosificación , Análisis de Regresión , Respiración ArtificialRESUMEN
The edema formation in nephrotic syndrome (NS) is associated with a blunted response to atrial natriuretic peptide (ANP). The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R). We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS). Urinary sodium, cyclic guanosine monophosphate (cGMP) excretion, and D1R protein expression and localization in renal tubules were evaluated in PAN-NS and control rats before and during volume expansion (VE). The effects of zaprinast (phosphodiesterase type 5 inhibitor), alone or in combination with Sch-23390 (D1R antagonist), were examined in both groups. The increased natriuresis and urinary cGMP excretion evoked by acute VE were blunted in PAN-NS despite increased levels of circulating ANP. This was accompanied in PAN-NS by a marked decrease of D1R expression in the renal tubules. Infusion of zaprinast in PAN-NS resulted in increased urinary excretion of cGMP and sodium to similar levels of control rats and increased expression of D1R in the plasma membrane of renal tubular cells. Combined administration of Sch-23390 and zaprinast prevented natriuresis and increased cGMP excretion induced by zaprinast alone. We conclude that D1R may play a major role in the ANP resistance observed in PAN-NS.
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Factor Natriurético Atrial/metabolismo , Natriuresis/efectos de los fármacos , Receptores de Dopamina D1/biosíntesis , Sodio/metabolismo , Animales , Benzazepinas/administración & dosificación , GMP Cíclico/orina , Tasa de Filtración Glomerular , Homeostasis , Riñón/metabolismo , Riñón/patología , Masculino , Síndrome Nefrótico/inducido químicamente , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/patología , Purinonas/administración & dosificación , Puromicina Aminonucleósido/toxicidad , Ratas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismoRESUMEN
Melanocyte-stimulating hormones, α-, ß- and γ-MSH, regulate important physiological functions including energy homeostasis, inflammation and sodium metabolism. Previous studies have shown that α-MSH increases sodium excretion and promotes vascular function in rodents, but it is unexplored whether these characteristics of α-MSH could translate into therapeutic benefits in the treatment of hypertension. Therefore, we first assessed the diuretic and natriuretic properties of the stable α-MSH analogue [Nle(4), D-Phe(7)]-α-MSH (NDP-α-MSH) and investigated whether it has protective effects in deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Adult male C57Bl/6N mice were subjected to DOCA-salt treatment and randomized to receive intraperitoneal injections of either saline as vehicle or NDP-α-MSH (0.3 mg/kg/day for 14 days) starting 7 days after the DOCA-salt treatment. Systemic hemodynamics, serum and urine electrolytes, and oxidative stress markers were assessed in control sham-operated and DOCA-salt mice. NDP-α-MSH elicited marked diuretic and natriuretic responses that were reversible with the MC3/4 receptor antagonist SHU9119. Chronic NDP-α-MSH treatment attenuated blood pressure elevation in DOCA-salt mice without affecting the blood pressure of normotensive control animals. Owing to the enhanced sodium excretion, NDP-α-MSH-treated mice were protected from DOCA-salt-induced hypernatremia. DOCA-salt treatment mildly increased oxidative stress at the tissue level, but NDP-α-MSH had no significant effects on the oxidative stress markers. In conclusion, treatment with NDP-α-MSH increases urinary sodium excretion and protects against DOCA-salt-induced hypertension. These findings point to the potential future use of α-MSH analogues in the treatment of hypertension.
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Presión Sanguínea , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , alfa-MSH/análogos & derivados , Animales , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/orina , Acetato de Desoxicorticosterona , Diuresis/efectos de los fármacos , Hipernatremia/tratamiento farmacológico , Hipernatremia/fisiopatología , Hipertensión/inducido químicamente , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones Endogámicos C57BL , Natriuresis/efectos de los fármacos , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor de Melanocortina Tipo 3/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Transducción de Señal/efectos de los fármacos , Telemetría , alfa-MSH/administración & dosificación , alfa-MSH/farmacología , alfa-MSH/uso terapéuticoRESUMEN
The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa(1)-vasotocin (dAVT), Mpa(1)-Arg(4)-vasotocin (dAAVT) and Mpa(1)-DArg(8)-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V1a agonist (Phe(2)-Ile(3)-Orn(8)-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V2 agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V1a antagonist (Pmp(1)-Tyr(Me)(2)-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V2 antagonist (Pmp(1)-DIle(2)-Ile(4)-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V1a or V1a-like receptor for natriuretic effect and V2 or V2-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones.