Title: The hypotensive effect of activated apelin receptor is correlated with \b{eta}-arrestin recruitment,
Abstract: The apelinergic system is an important player in the regulation of both
vascular tone and cardiovascular function, making this physiological system an
attractive target for drug development for hypertension, heart failure and
ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in
humans whilst reducing peripheral vascular resistance. In this study, we
investigated the signaling pathways through which apelin exerts its hypotensive
action. We synthesized a series of apelin-13 analogs whereby the C-terminal
Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells
expressing APJ, we evaluated the relative efficacy of these compounds to
activate G{\alpha}i1 and G{\alpha}oA G-proteins, recruit \b{eta}-arrestins 1
and 2 (\b{eta}arrs), and inhibit cAMP production. Calculating the transduction
ratio for each pathway allowed us to identify several analogs with distinct
signaling profiles. Furthermore, we found that these analogs delivered i.v. to
Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two
compounds lost their ability to lower blood pressure, while other analogs
significantly reduced blood pressure as apelin-13. Interestingly, analogs that
did not lower blood pressure were less effective at recruiting \b{eta}arrs.
Finally, using Spearman correlations, we established that the hypotensive
response was significantly correlated with \b{eta}arr recruitment but not with
G protein- dependent signaling. In conclusion, our results demonstrated that
the \b{eta}arr recruitment potency is involved in the hypotensive efficacy of
activated APJ.