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JAMA Dermatol ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32876649
PLoS One ; 14(5): e0215221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120888


Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.

Avaliação Pré-Clínica de Medicamentos/normas , Relatório de Pesquisa/normas , Analgésicos/uso terapêutico , Animais , Bases de Dados Factuais , Guias como Assunto , Dor/tratamento farmacológico
J Physiol ; 593(5): 1127-46, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25641115


Natriuretic peptides (NPs) are critical regulators of the cardiovascular system that are currently viewed as possible therapeutic targets for the treatment of heart disease. Recent work demonstrates potent NP effects on cardiac electrophysiology, including in the sinoatrial node (SAN) and atria. NPs elicit their effects via three NP receptors (NPR-A, NPR-B and NPR-C). Among these receptors, NPR-C is poorly understood. Accordingly, the goal of this study was to determine the effects of NPR-C ablation on cardiac structure and arrhythmogenesis. Cardiac structure and function were assessed in wild-type (NPR-C(+/+)) and NPR-C knockout (NPR-C(-/-)) mice using echocardiography, intracardiac programmed stimulation, patch clamping, high-resolution optical mapping, quantitative polymerase chain reaction and histology. These studies demonstrate that NPR-C(-/-) mice display SAN dysfunction, as indicated by a prolongation (30%) of corrected SAN recovery time, as well as an increased susceptibility to atrial fibrillation (6% in NPR-C(+/+) vs. 47% in NPR-C(-/-)). There were no differences in SAN or atrial action potential morphology in NPR-C(-/-) mice; however, increased atrial arrhythmogenesis in NPR-C(-/-) mice was associated with reductions in SAN (20%) and atrial (15%) conduction velocity, as well as increases in expression and deposition of collagen in the atrial myocardium. No differences were seen in ventricular arrhythmogenesis or fibrosis in NPR-C(-/-) mice. This study demonstrates that loss of NPR-C results in SAN dysfunction and increased susceptibility to atrial arrhythmias in association with structural remodelling and fibrosis in the atrial myocardium. These findings indicate a critical protective role for NPR-C in the heart.

Fibrilação Atrial/genética , Fibrilação Atrial/metabolismo , Receptores do Fator Natriurético Atrial/genética , Nó Sinoatrial/metabolismo , Potenciais de Ação , Animais , Células Cultivadas , Colágeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Receptores do Fator Natriurético Atrial/metabolismo , Nó Sinoatrial/fisiopatologia
J Mol Cell Cardiol ; 53(5): 715-24, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22960454


Natriuretic peptides, including BNP and CNP, elicit their effects via two guanylyl cyclase-linked receptors denoted NPR-A and NPR-B as well as a third receptor, NPR-C. The relative contributions of these receptors to the overall effects of NPs on heart rate (HR) and sinoatrial node (SAN) function are very poorly understood. The effects of BNP and CNP (10-500 nM) on HR and SAN myocyte spontaneous action potential (AP) firing were studied using wildtype mice and mice lacking functional NPR-C receptors (NPR-C(-/-)). In basal conditions and 10 nM doses of the ß-adrenergic receptor (ß-AR) agonist isoproterenol (ISO) BNP and CNP increased HR and AP firing in SAN myocytes. The NPR-C selective agonist cANF (10-500 nM) had no effects in basal conditions, but decreased HR and SAN AP frequency in the presence of ISO. These effects of cANF were completely absent in NPR-C(-/-) mice. Strikingly, in the presence of 1 µM doses of ISO, BNP and CNP switched to causing decreases in HR and SAN AP frequency. These decreases were not as large as those elicited by cANF and were absent in NPR-C(-/-) hearts, where BNP instead elicited a further increase in HR. Inhibition of NPR-A with A71915, in the presence of 1 µM ISO, enabled BNP to signal exclusively through NPR-C and to decrease HR as effectively as cANF. Together these data demonstrate that BNP and CNP affect HR and SAN function by activating multiple receptor subtypes. NPR-A/B mediate increases in HR and SAN function, but these effects are opposed by NPR-C, which plays an increasingly important signaling role in the presence of ß-AR stimulation.

Frequência Cardíaca/efeitos dos fármacos , Peptídeo Natriurético Encefálico/fisiologia , Peptídeo Natriurético Tipo C/fisiologia , Nó Sinoatrial/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Fator Natriurético Atrial/farmacologia , Células Cultivadas , Coração/efeitos dos fármacos , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Peptídeo Natriurético Encefálico/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores do Fator Natriurético Atrial/agonistas , Receptores do Fator Natriurético Atrial/antagonistas & inibidores , Receptores do Fator Natriurético Atrial/metabolismo , Nó Sinoatrial/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia