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@inproceedings{Davenport:2018:10.1161/RES.0000000000000236,
author = {Davenport, AP and Brame, AL and Kuc, RE and Cheriyan, J and Glen, RR and Wilkinson, IB and Maguire, JJ},
doi = {10.1161/RES.0000000000000236},
pages = {E75--E76},
publisher = {American Heart Association},
title = {First In human study of a novel biased apelin receptor ligand, MM54, a G-alpha(i) agonist/beta-arrestin antagonist},
url = {http://dx.doi.org/10.1161/RES.0000000000000236},
year = {2018}
}

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TY  - CPAPER
AB  - Introduction: The peptide apelin acts via G proteins to cause beneficial vasodilation and potent positive inotropy to ameliorate pulmonary arterial hypertension in humans and animal models. Apelin is internalised via β-arrestin. In contrast, with loss of endogenous apelin, its receptor acts as a mechanosensor, stimulating β-arrestin to induce detrimental cardiac hypertrophy. Our aim was to characterise the action of our apelin ligand, MM54 that in cell based assays blocks β-arrestin but activates the Gαi protein pathway, in this first in human study. Method: Competition binding in human heart (n=3) used [I125] [Pyr1]apelin-13 (0.1nmol/L). β-arrestin recruitment, receptor internalization and forskolin-induced cAMP inhibition were measured in CHO-K1 cells expressing human apelin receptor. Forearm blood flow was measured in 9 volunteers using venous occlusion plethysmography at baseline and at 4 incremental doses (1, 10, 30, 100 nmol/min) of MM54, each for eight minutes. The Aellig hand vein technique was used to measure the effect of 3 incremental doses (3, 30, 300 nmol/min) of MM54 for 15 min on veins pre-constricted with noradrenaline in 6 individuals compared with 8 controls. Data are mean+SEM, n≥3. Results: MM54 had an affinity of pKi = 6.50±0.03. In β-arrestin (pKB 6.93±0.15) and receptor internalization assays (pKB 5.89±0.06) MM54 was an antagonist, but activated the G protein pathway (pD2±SEM 5.86+0.23). At the highest concentration (100 nmol/min), MM54 caused a significant absolute increase in forearm blood flow compared to control arm, representing a 76 % change from baseline (P<0.01, ANOVA with repeated measures with Dunnett’s post hoc analysis on untransformed data). In the hand vein, MM54 caused a significant concentration dependent dilatation in veins over the concentration range tested, with the highest dose causing 57% reversal (P<0.01). Conclusion: At the cellular level, the resu
AU  - Davenport,AP
AU  - Brame,AL
AU  - Kuc,RE
AU  - Cheriyan,J
AU  - Glen,RR
AU  - Wilkinson,IB
AU  - Maguire,JJ
DO  - 10.1161/RES.0000000000000236
EP  - 76
PB  - American Heart Association
PY  - 2018///
SN  - 0009-7330
SP  - 75
TI  - First In human study of a novel biased apelin receptor ligand, MM54, a G-alpha(i) agonist/beta-arrestin antagonist
UR  - http://dx.doi.org/10.1161/RES.0000000000000236
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000454198400037&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.ahajournals.org/doi/10.1161/RES.0000000000000236
UR  - http://hdl.handle.net/10044/1/79718
ER  -

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