ABSTRACT
RATIONALE: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7). OBJECTIVE: To characterize a novel component of the RAS, alamandine. METHODS AND RESULTS: Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro(7)-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand ß-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/ß-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines. CONCLUSIONS: The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders.
Subject(s)
Angiotensin I/chemistry , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Drug Discovery , Oligopeptides/chemistry , Peptide Fragments/chemistry , Renin-Angiotensin System/physiology , Angiotensin I/physiology , Angiotensin II/analogs & derivatives , Angiotensin II/chemistry , Angiotensin II/physiology , Angiotensin-Converting Enzyme 2 , Animals , Antihypertensive Agents/isolation & purification , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Drug Discovery/methods , Humans , Male , Oligopeptides/physiology , Peptide Fragments/physiology , Peptidyl-Dipeptidase A/physiology , Proto-Oncogene Mas , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/physiology , Rats , Rats, Inbred F344 , Rats, Inbred SHR , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/physiologyABSTRACT
The Na+/K+-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na+/K+-ATPase. Here, we conducted a systematic review of the in vitro effects of cardiotonic steroids on Ca2+ in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca2+ signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na+/Ca2+ exchanger and increased intracellular Ca2+, other effects have been reported. Ouabain-mediated Ca2+ signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca2+ increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498, identifier CRD42020204498.
ABSTRACT
BACKGROUND AND OBJECTIVES: The current preoperative fasting guidelines allow fluid intake up to 2hours before surgery. The aim of this study was to evaluate the gastric volume of volunteers after an overnight fast and compare it with the gastric volume 2hours after ingestion of 200 and 500mL of isotonic solution, by means of ultrasound assessment. METHOD: Eighty volunteers underwent gastric ultrasound at three times: after 8hours of fasting; 2hours after ingestion of 200mL isotonic saline, followed by the first scan; and on another day, 2hours after ingestion of 500mL of the same solution after an overnight fast. The evaluation was quantitative (antrum area and gastric volume, and the ratio of participants' gastric volume/weight) and qualitative (absence or presence of gastric contents on right lateral decubitus and supine positions. A p-value<0.05 was considered significant). RESULTS: There was no difference in quantitative variables at measurement times (p>0.05). Five volunteers (6.25%) had a volume/weight over 1.5mL.kg-1 at fasting and 2hours after ingestion of 200mL and 6 (7.5%) after 500mL. Qualitatively, the presence of gastric fluid occurred in more volunteers after fluid ingestion, especially 500mL (18.7%), although not statistically significant. CONCLUSION: Ultrasound assessment of gastric volume showed no significant difference, both qualitative and quantitative, 2h after ingestion of 200mL or 500mL of isotonic solution compared to fasting, although gastric fluid content has been identified in more volunteers, especially after ingestion of 500mL isotonic solution.
Subject(s)
Isotonic Solutions/administration & dosage , Stomach/anatomy & histology , Stomach/diagnostic imaging , Adult , Cross-Sectional Studies , Eating , Female , Humans , Male , Organ Size , Prospective Studies , Stomach/physiology , UltrasonographyABSTRACT
Abstract Background and objectives: The current preoperative fasting guidelines allow fluid intake up to 2 h before surgery. The aim of this study was to evaluate the gastric volume of volunteers after an overnight fast and compare it with the gastric volume 2 h after ingestion of 200 and 500 mL of isotonic solution, by means of ultrasound assessment. Method: Eighty volunteers underwent gastric ultrasound at three times: after 8 h of fasting; 2 h after ingestion of 200 mL isotonic saline, followed by the first scan; and on another day, 2 h after ingestion of 500 mL of the same solution after an overnight fast. The evaluation was quantitative (antrum area and gastric volume, and the ratio of participants' gastric volume/weight) and qualitative (absence or presence of gastric contents on right lateral decubitus and supine positions. A p-value < 0.05 was considered significant). Results: There was no difference in quantitative variables at measurement times (p > 0.05). Five volunteers (6.25%) had a volume/weight over 1.5 mL kg-1 at fasting and 2 h after ingestion of 200 mL and 6 (7.5%) after 500 mL. Qualitatively, the presence of gastric fluid occurred in more volunteers after fluid ingestion, especially 500 mL (18.7%), although not statistically significant. Conclusion: Ultrasound assessment of gastric volume showed no significant difference, both qualitative and quantitative, 2 h after ingestion of 200 mL or 500 mL of isotonic solution compared to fasting, although gastric fluid content has been identified in more volunteers, especially after ingestion of 500 mL isotonic solution.
Resumo Justificativa e objetivos: As diretrizes recentes de jejum pré-operatório permitem a ingestão de líquidos até 2 horas antes da cirurgia. O objetivo do presente estudo foi, por meio de ultrassonografia gástrica, avaliar o volume gástrico de voluntários após jejum noturno e comparar com o volume gástrico duas horas após a ingestão de 200 e 500 ml de solução isotônica. Método: Foram submetidos à ultrassonografia gástrica 80 voluntários em três momentos: após jejum de 8 horas; 2 horas após a ingestão de 200 ml de solução isotônica, seguida do primeiro exame; e, em outro dia, 2 horas após a ingestão de 500 ml da mesma solução, após jejum noturno. A avaliação foi quantitativa (área do antro e volume gástricos e relação volume gástrico/peso dos participantes) e qualitativa, pela ausência ou presença de conteúdo gástrico nas posições de decúbito lateral direito e supina. Foi considerado significante p < 0,05. Resultados: Não houve diferença nas variáveis quantitativas nos três momentos estudados (p > 0,05). Cinco voluntários (6,25%) apresentaram um volume/peso superior a 1,5 ml.kg-1 em jejum e 2 horas após a ingestão de 200 ml e seis (7,5%) após 500 ml. Qualitativamente, a presença de líquido gástrico ocorreu em mais voluntários após a ingestão de líquidos, principalmente de 500 ml (18,7%), embora sem significância estatística. Conclusão: O volume gástrico pela ultrassonografia não apresenta diferença significativa tanto qualitativa quanto quantitativa, 2 horas após a ingestão de 200 ml ou de 500 ml de solução isotônica em comparação com o jejum, embora conteúdo líquido gástrico tenha sido identificado em mais voluntários, principalmente após a ingestão de 500 ml de solução isotônica.