Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects.
Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling cardiovascular functions and water balance. Because the in vivo apelin half-life is in the minute range, we aimed to identify metabolically stable apelin-17 (K17F) analogs. We generated P92 by classic chemical substitutions and LIT01-196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half-life >24 h for LIT01-196) than K17F (4.6 min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aortas and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water-deprived mice, P92 and LIT01-196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In summary, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/hyponatremic disorders.-Gerbier, R., Alvear-Perez, R., Margathe, J.-F., Flahault, A., Couvineau, P., Gao, J., De Mota, N., Dabire, H., Li, B., Ceraudo, E., Hus-Citharel, A., Esteoulle, L., Bisoo, C., Hibert, M., Berdeaux, A., Iturrioz, X., Bonnet, D., Llorens-Cortes, C. Development of original metabolically stable apelin-17 analogs with diuretic and cardiovascular effects.
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Romain
R
Gerbier
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Rodrigo
R
Alvear-Perez
Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France; and.
Jean-Francois
JF
Margathe
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Adrien
A
Flahault
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Pierre
P
Couvineau
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Ji
J
Gao
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Nadia
N
De Mota
INSERM Unité 955, Faculty of Medicine, University of Paris Est, Créteil, France.
Hubert
H
Dabire
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Bo
B
Li
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Emilie
E
Ceraudo
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Annette
A
Hus-Citharel
Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France; and.
Lucie
L
Esteoulle
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Cynthia
C
Bisoo
Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France; and.
Marcel
M
Hibert
INSERM Unité 955, Faculty of Medicine, University of Paris Est, Créteil, France.
Alain
A
Berdeaux
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France.
Xavier
X
Iturrioz
Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France; and.
Dominique
D
Bonnet
Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM Unité 1050, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241, College de France, Paris, France; c.llorens-cortes@college-de-france.fr.
Catherine
C
Llorens-Cortes
D000595:Amino Acid Sequence; D000818:Animals; D000075244:Apelin Receptors; D016466:CHO Cells; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction
D000075244:Apelin Receptors; C491284:Aplnr protein, rat; D002317:Cardiovascular Agents; D004232:Diuretics; D010455:Peptides; D043562:Receptors, G-Protein-Coupled
blood pressure; cardiac contractility; vascular reactivity; vasopressin and diuresis