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Hypertension ; 74(2): 323-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177906


Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: . Unique identifier: NCT00810732.

Doenças Cardiovasculares/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Nifedipino/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Resultado do Tratamento
Nanotoxicology ; 10(7): 981-91, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27027807


In biological fluids nanoparticles bind a range of molecules, particularly proteins, on their surface. The resulting protein corona influences biological activity and fate of nanoparticle in vivo. Corona composition is often determined by the biological milieu encountered at the entry portal into the body, and, can therefore, depend on the route of exposure to the nanoparticle. For environmental nanoparticles where exposure is by inhalation, this will be lung lining fluid. This study examined plasma and bronchoalveolar fluid (BALF) protein binding to engineered and environmental nanoparticles. We hypothesized that protein corona on nanoparticles would influence nanoparticle uptake and subsequent pro-inflammatory biological response in macrophages. All nanoparticles bound plasma and BALF proteins, but the profile of bound proteins varied between nanoparticles. Focusing on diesel exhaust nanoparticles (DENP), we identified proteins bound from plasma to include fibrinogen, and those bound from BALF to include albumin and surfactant proteins A and D. The presence on DENP of a plasma-derived corona or one of purified fibrinogen failed to evoke an inflammatory response in macrophages. However, coronae formed in BALF increased DENP uptake into macrophages two fold, and increased nanoparticulate carbon black (NanoCB) uptake fivefold. Furthermore, a BALF-derived corona increased IL-8 release from macrophages in response to DENP from 1720 ± 850 pg/mL to 5560 ± 1380 pg/mL (p = 0.014). These results demonstrate that the unique protein corona formed on nanoparticles plays an important role in determining biological reactivity and fate of nanoparticle in vivo. Importantly, these findings have implications for the mechanism of detrimental properties of environmental nanoparticles since the principle route of exposure to such particles is via the lung.

Líquido da Lavagem Broncoalveolar/química , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas/toxicidade , Coroa de Proteína/metabolismo , Emissões de Veículos/toxicidade , Proteínas Sanguíneas/química , Linhagem Celular , Humanos , Interleucina-8/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Nanopartículas/química , Tamanho da Partícula , Ligação Proteica , Propriedades de Superfície , Emissões de Veículos/análise
Am J Gastroenterol ; 102(10): 2238-46, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17573796


OBJECTIVE: The safety and efficacy of NaP tablets have not been compared with 2L PEG lavage solution. A multicenter, investigator-blinded study was conducted to compare the colon-cleansing efficacy of a new NaP tablet formulation with that of 2L PEG solution plus bisacodyl tablets in adults undergoing colonoscopy. METHODS: A total of 481 patients were randomized to receive either 32 tablets (48 g) of NaP or 2L PEG solution plus 4 (20 mg) bisacodyl tablets. Quality of colon cleansing was assessed using a 4-point scale (1 = excellent, 2 = good, 3 = fair, and 4 = inadequate), and the primary efficacy end point was mean overall colon-cleansing score. Safety assessments included recording of adverse events and changes in biochemical tests and vital signs. RESULTS: A total of 411 patients were included in the efficacy analysis. The mean overall and ascending colon-cleansing scores for NaP tablets were significantly better than PEG plus bisacodyl (overall 1.5 vs 1.8, ascending 1.4 vs 1.8, P < 0.0001 for both). Patients treated with NaP tablets experienced significantly fewer adverse events (66%vs 82%, P= 0.0003) and gastrointestinal symptoms (64%vs 79%, P= 0.0001) compared with patients receiving PEG plus bisacodyl. Patients receiving NaP tablets were significantly less likely to experience abdominal distention, abdominal pain, and vomiting than patients receiving PEG plus bisacodyl (P < 0.0012). Transient fluctuations in laboratory parameters were observed in both treatment groups; however, the fluctuations were more common and of greater magnitude in the NaP group particularly in phosphorous, sodium, and potassium. CONCLUSION: The colon-cleansing efficacy of the new 32-tablet NaP dosing regimen in this study was found to be significantly better than the 2L PEG solution plus bisacodyl tablets regimen. The 32-tablet NaP dosing regimen was associated with fewer adverse events. As expected electrolyte shifts were more common and of greater magnitude in the NaP group compared with the PEG plus bisacodyl group; however, both treatment groups demonstrated significant changes in electrolytes and creatinine.

Bisacodil/administração & dosagem , Catárticos/administração & dosagem , Colonoscopia , Fosfatos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tensoativos/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Comprimidos , Resultado do Tratamento
Am J Physiol Regul Integr Comp Physiol ; 289(3): R871-6, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15890791


Calcium/calmodulin-dependent kinase II (CaMKII) is an ubiquitous second messenger that is highly expressed in neurons, where it has been implicated in some of the pathways regulating neuronal discharge as well as N-methyl-d-aspartate receptor-mediated synaptic plasticity. The full expression of the mammalian hypoxic ventilatory response (HVR) requires intact central relays within the nucleus of the solitary tract (NTS), and neural transmission of hypoxic afferent input is mediated by glutamatergic receptor activity, primarily through N-methyl-D-aspartate receptors. To examine the functional role of CaMKII in HVR, KN-93, a highly selective antagonist of CaMKII, was microinjected in the NTS via bilaterally placed osmotic pumps in freely behaving adult male Sprague-Dawley rats for 3 days. Vehicle-loaded osmotic pumps were surgically placed in control animals, and adequate placement of cannulas was ascertained for all animals. HVR was measured using whole body plethysmography during exposure to 10% O(2)-balance N(2) for 20 min. Compared with control rats, KN-93 administration elicited marked attenuations of peak HVR (pHVR) but did not modify normoxic minute ventilation. Differences in pHVR were primarily attributable to diminished respiratory frequency recruitments during pHVR without significant differences in tidal volume. These findings indicate that CaMKII activation in the NTS mediates respiratory frequency components of the ventilatory response to acute hypoxia; however, CaMKII activity does not appear to underlie components of normoxic ventilation.

Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Hipóxia/fisiopatologia , Respiração , Núcleo Solitário/fisiopatologia , Animais , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Masculino , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Respiração/efeitos dos fármacos , Sulfonamidas/farmacologia