Objective-Angiotensin peptides play a central role in cardiovascular physiology and pathology. Among these peptides, angiotensin II (Ang II) has been investigated most intensively. However, further angiotensin peptides such as Ang 1-7, Ang III, and Ang IV also contribute to vascular regulation, and may elicit additional, different, or even opposite effects to Ang II. Here, we describe a novel Ang II-related, strong vasoconstrictive substance in plasma from healthy humans and end-stage renal failure patients. ]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp 1 . Ang A has the same affinity to the AT 1 receptor as Ang II, but a higher affinity to the AT 2 receptor. In the isolated perfused rat kidney, Ang A revealed a smaller vasoconstrictive effect than Ang II, which was not modified in the presence of the AT2 receptor antagonist PD 123319, suggesting a lower intrinsic activity at the AT 1 receptor. Ang II and Ang A concentrations in plasma of healthy subjects and end-stage renal failure patients were determined by matrix-assisted laser desorption/ionisation mass-analysis, because conventional enzyme immunoassay for Ang II quantification did not distinguish between Ang II and Ang A. In healthy subjects, Ang A concentrations were less than 20% of the Ang II concentrations, but the ratio Ang A / Ang II was higher in end-stage renal failure patients. Conclusion-Ang
BackgroundWhile randomized controlled trials (RCTs) are based on strict inclusion/exclusion criteria, non-interventional studies (NISs) might provide additional information to guide management in patients more representative to the real-world setting. The aim of this study was to compare baseline characteristics of patients receiving intravitreal treatment in the NIS OCEAN with those from published RCTs.MethodsThe ongoing OCEAN study enrolled patients treated with ranibizumab for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) or branch/central retinal vein occlusion (B/CRVO). Baseline patient characteristics were compared by indication within the OCEAN cohort. Furthermore, the characteristics were set in reference to those of published RCTs in the same indications. Confidence intervals (CIs) were calculated and assessed for statistically significant differences as indicated by non-overlapping CIs.ResultsPatient characteristics in the NIS OCEAN were evaluated for 3,614 patients with nAMD, 1,211 with DME, 204 with BRVO and 121 with CRVO. Between these groups, significant differences in mean age, gender distributions, and mean baseline VA were seen, reflecting known differences between the indications.Compared to the patient characteristics of published RCTs (trials selected by literature search: nAMD: 13 RCTs, DME: 9, RVO: 5), the OCEAN patients’ mean age was significantly higher in every indication. The gender distributions across the trials were comparable, with only few differences between OCEAN and the RCTs. Regarding the mean baseline VA, notable differences were found in nAMD and in DME, with VA significantly higher in some RCTs and lower in others.ConclusionsThe described differences underline the complementarity of NISs and RCTs. OCEAN covers a broader spectrum and more variability of patients than do RCTs. As baseline values may have impact on the treatment response (ceiling effect), there is an ongoing need for research in all patient subgroups. Country-specific assessments of patient populations can better reflect the real-world situation. NISs can deliver insights that RCTs may not, as NISs can include non-typical patients, patients with comorbidities, a broader age spectrum and patients of various disease stages.Trial registrationThe NIS OCEAN was registered on www.clinicaltrials.gov (identifier: NCT02194803).Electronic supplementary materialThe online version of this article (doi:10.1186/s12886-017-0401-y) contains supplementary material, which is available to authorized users.
BACKGROUND AND PURPOSEPurinergic signalling plays an important role in vascular tone regulation in humans. We have identified uridine adenosine tetraphosphate (Up4A) as a novel and highly potent endothelial-derived contracting factor. Up4A induces strong vasoconstrictive effects in the renal vascular system mainly by P2X1 receptor activation. However, other purinoceptors are also involved and were analysed here. EXPERIMENTAL APPROACHThe rat isolated perfused kidney was used to characterize vasoactive actions of Up4A. KEY RESULTSAfter desensitization of the P2X1 receptor by a,b-methylene ATP (a,b-meATP), Up4A showed dose-dependent P2Y2-mediated vasoconstriction. Continuous perfusion with Up4A evoked a biphasic vasoconstrictor effect: there was a strong and rapidly desensitizing vasoconstriction, inhibited by P2X1 receptor desensitization. In addition, there is a long-lasting P2Y2-mediated vasoconstriction. This vasoconstriction could be blocked by suramin, but not by PPADS or reactive blue 2. In preparations of the rat isolated perfused kidney model with an elevated vascular tone, bolus application of Up4A showed a dose-dependent vasoconstriction that was followed by a dose-dependent vasodilation. The vasoconstriction was in part sensitive to P2X1 receptor desensitization by a,b-meATP, and the remaining P2Y2-mediated vasoconstriction was only inhibited by suramin. The Up4A-induced vasodilation depended on activation of nitric oxide synthases, and was mediated by P2Y1 and P2Y2 receptor activation. CONCLUSIONS AND IMPLICATIONSUp4A activated P2X1 and P2Y2 receptors to act as a vasoconstrictor, whereas endothelium-dependent vasodilation was induced by P2Y1/2 receptor activation. Up4A might be of relevance in the physiology and pathophysiology of vascular tone regulation.Abbreviations a,b-meATP, a,b-methylene ATP; AngII, angiotensin II; ApnA, diadenosine-n-phophate (n: number of phosphates); ApnG, adenosine-guanosine-n-phosphate (n: number of phosphates); ApoE, apolipoprotein E; CI, confidence interval; DMSO, dimethyl sulphoxide; eNOS, endothelial NOS; GpnG, diguanosine-n-phosphate (n: number of phosphates); L-NAME, N G -nitro-L-arginine methyl ester; MAP, mean arterial blood pressure; MCP-1, monocyte chemoattractant protein-1; MRS2179, 2′-deoxy-N6-methyladenosine 3′,5′-bisphosphate; PPADS, pyridoxal-phosphate-6-azophenyl-2;4-disulphonic acid; RB2, reactive blue 2; Up4A, uridine adenosine tetraphosphate BJP British Journal of Pharmacology
It is very well established that purinergic signaling plays a relevant role in vascular physiology and pathophysiology. Recently, a new purinoceptor agonist uridine adenosine tetraphosphate (Up(4)A) has been identified as a highly potent endothelial-derived contracting factor (EDCF). The purpose of the study was to investigate Up(4)A's influence on pro-inflammatory mechanisms. An early component of the inflammatory response in atherogenesis is the oxidative stress-induced formation of monocyte chemoattractant protein-1 (MCP-1). Here, we investigated the influence of Up(4)A on MCP-1 formation and characterized the underlying signaling transduction mechanisms in rat vascular smooth muscle cells (VSMCs). Up(4)A induced MCP-1 expression and secretion in VSMCs via the activation of P2Y(2) in a concentration-dependent manner. MCP-1 formation depends on generation of reactive oxygen species (ROS). To determine whether the predominant source of ROS in the vasculature, the NAD(P)H oxidase (Nox), is involved, we used different approaches. The ROS scavenger, tiron, the Nox inhibitor, apocynin and diphenyl-iodonium, as well as Nox1 knockdown, diminished the Up(4)A-induced MCP-1 formation. Rac1 activation and p47(phox) translocation from cytosol to the plasma membrane-both required for assembling and activation of Nox, were stimulated by Up(4)A. ERK1/2 and p38 activation is essential for the intracellular signal transduction. In summary, Up(4)A induced Nox1-dependent ROS generation, which further stimulated MCP-1 formation via MAPK phosphorylation in VSMCs. This process requires the activation of the G-protein coupled receptor P2Y(2). Therefore, Up(4)A is not only a potent EDCF but also a potent inductor of pro-inflammatory response in the vascular wall.
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