Evidence map›Paper›PMID 25712721›Full record

ArticleHypertension (Dallas, Tex. : 1979)2015

Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.

Aimee L Brame, Janet J Maguire, Peiran Yang, Alex Dyson, Rubben Torella, Joseph Cheriyan, Mervyn Singer, Robert C Glen, Ian B Wilkinson, Anthony P Davenport

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hypertension (Dallas, Tex. : 1979), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.

0numbers the graph read from it
0cells of the map it votes in
68citing papers in PubMed
16.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

68 citing papers in PubMed, 152 citations in OpenAlex.

  1. Trial
  2. Article
  3. Article
  4. Review
  5. Review
  6. Article
  7. Review
  8. The Apelinergic System in Kidney Disease: Novel Perspectives.International journal of molecular sciences · 2025
    Review
  9. A Metabolically Stable Apelin-13 Analog Acting as a Potent IInternational journal of molecular sciences · 2025
    Article
  10. Review
  11. Article
  12. Article
  13. Review
  14. Article
  15. Review
  16. Article
  17. Review
  18. Review
  19. Review
  20. Signaling Modulation via Minimal C-Terminal Modifications of Apelin-13.ACS pharmacology & translational science · 2023
    Article

8 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Aimee L BrameFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Janet J MaguireFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Peiran YangFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Alex DysonFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Rubben TorellaFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Joseph CheriyanFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Mervyn SingerFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Robert C GlenFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Ian B WilkinsonFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.).
Anthony P DavenportFrom the Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK (A.L.B., J.J.M., P.Y., J.C., I.B.W., A.P.D.); Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK (A.D., M.S.); and Unilever Centre for Molecular Sciences Informatics, Department of Chemistry, University of. Cambridge, Cambridge, UK (R.T., R.C.G.). apd10@medschl.cam.ac.uk.
Bury College · GBUniversity College London · GB

Funding

British Heart Foundation FS/12/8/29377British Heart Foundation PG/09/050/27734Department of HealthMedical Research Council MC_PC_12012Medical Research Council MC_PC_13059Wellcome Trust 085686Wellcome Trust 096822Wellcome Trust 096822/Z/11/Z
6 · The paper itself

Abstract

[Pyr(1)]apelin-13 is an endogenous vasodilator and inotrope but is downregulated in pulmonary hypertension and heart failure, making the apelin receptor an attractive therapeutic target. Agonists acting at the same G-protein-coupled receptor can be engineered to stabilize different conformational states and function as biased ligands, selectively stimulating either G-protein or β-arrestin pathways. We used molecular dynamics simulations of apelin/receptor interactions to design cyclic analogues and identified MM07 as a biased agonist. In β-arrestin and internalization assays (G-protein-independent), MM07 was 2 orders of magnitude less potent than [Pyr(1)]apelin-13. In a G-protein-dependent saphenous vein contraction assay, both peptides had comparable potency (pD2:[Pyr(1)]apelin-13 9.93±0.24; MM07 9.54±0.42) and maximum responses with a resulting bias for MM07 of ≈350- to 1300-fold for the G-protein pathway. In rats, systemic infusions of MM07 (10-100nmol) caused a dose-dependent increase in cardiac output that was significantly greater than the response to [Pyr(1)]apelin-13. Similarly, in human volunteers, MM07 produced a significant dose-dependent increase in forearm blood flow with a maximum dilatation double that is seen with [Pyr(1)]apelin-13. Additionally, repeated doses of MM07 produced reproducible increases in forearm blood flow. These responses are consistent with a more efficacious action of the biased agonist. In human hand vein, both peptides reversed an established norepinephrine constrictor response and significantly increased venous flow. Our results suggest that MM07 acting as a biased agonist at the apelin receptor can preferentially stimulate the G-protein pathway, which could translate to improved efficacy in the clinic by selectively stimulating vasodilatation and inotropic actions but avoiding activating detrimental β-arrestin-dependent pathways.

Indexed as

Research DesignAnimalsAntipyreticsApelin ReceptorsDisease Models, AnimalGTP-Binding ProteinsHumansHypertension, PulmonaryIntercellular Signaling Peptides and ProteinsMaleRatsRats, WistarReceptors, G-Protein-CoupledSaphenous VeinVasodilationAntipyreticsapelin 13, Pyr(1)-Apelin ReceptorsAplnr protein, ratGTP-Binding ProteinsIntercellular Signaling Peptides and ProteinsReceptors, G-Protein-Coupledpulmonary arterial hypertension[Pyr1]apelin-13β-arrestin G-protein coupled receptors

Identifiers

PMID25712721
PMCPMC4354462
OpenAlexW2109058223

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.