title: Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile.
abstract: Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine8-Vasopressin (LVP), able to counteract the splanchnic vasodilation. However, the complete pharmacological characterization of this drug with respect to the different vasopressin receptor subtypes is missing. We studied terlipressin intrinsic properties, focusing not only on V1A, but also on other vasopressin receptor subtypes. The experimental studies were conducted on rat and human cellular models. Binding experiments were performed on rat liver membranes and CHO cells transfected with the different human vasopressin receptor subtypes. Agonist status was assessed from inositol phosphate or cyclic AMP assays, and measurement of intracellular calcium variations, performed on cultured vascular smooth muscle cells from rat aorta and human uterine artery and CHO cells. Terlipressin binds to the rat and human V1A receptors with an affinity in the micromolar range, a value 120 fold lower than that of LVP. It induces a rapid and transient intracellular calcium increase, a robust stimulation of phospholipase C but with reduced maximal efficiencies as compared to LVP, indicating a partial V1A agonist property. In addition, terlipressin is also a full agonist of human V2 and V1B receptors, with also a micromomolar affinity.
  
  
  
  Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.
authors: Institut de Génomique Fonctionnelle, Département d'Endocrinologie, CNRS UMR 5203, INSERM U1191, Université de Montpellier, F-34094 Montpellier, France; Département d'Anesthésie Réanimation Arnaud de Villeneuve, Centre Hospitalier Régional et Universitaire, F-34295 Montpellier, France. Electronic address: p-colson@chu-montpellier.fr.
authors: Pascal H
authors: PH
authors: Colson
authors: PhyMedExp, INSERM U1046, CNRS UMR 9214, Université de Montpellier, F-34295 Montpellier, France. Electronic address: anne.virsolvy@inserm.fr.
authors: Anne
authors: A
authors: Virsolvy
authors: PhyMedExp, INSERM U1046, CNRS UMR 9214, Université de Montpellier, F-34295 Montpellier, France; Département d'Anesthésie Réanimation Arnaud de Villeneuve, Centre Hospitalier Régional et Universitaire, F-34295 Montpellier, France. Electronic address: p-gaudard@chu-montpellier.fr.
authors: Philippe
authors: P
authors: Gaudard
authors: PhyMedExp, INSERM U1046, CNRS UMR 9214, Université de Montpellier, F-34295 Montpellier, France. Electronic address: azzouz.charrabi@inserm.fr.
authors: Azzouz
authors: A
authors: Charrabi
authors: Institut de Génomique Fonctionnelle, Département d'Endocrinologie, CNRS UMR 5203, INSERM U1191, Université de Montpellier, F-34094 Montpellier, France. Electronic address: maithe.corbani@igf.cnrs.fr.
authors: Maithé
authors: M
authors: Corbani
authors: Institut de Génomique Fonctionnelle, Département d'Endocrinologie, CNRS UMR 5203, INSERM U1191, Université de Montpellier, F-34094 Montpellier, France. Electronic address: m.maniere@gmail.com.
authors: Maxime J
authors: MJ
authors: Manière
authors: PhyMedExp, INSERM U1046, CNRS UMR 9214, Université de Montpellier, F-34295 Montpellier, France. Electronic address: sylvain.richard@inserm.fr.
authors: Sylvain
authors: S
authors: Richard
authors: Institut de Génomique Fonctionnelle, Département d'Endocrinologie, CNRS UMR 5203, INSERM U1191, Université de Montpellier, F-34094 Montpellier, France. Electronic address: gilles.guillon@igf.cnrs.fr.
authors: Gilles
authors: G
authors: Guillon
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006530:Hepatorenal Syndrome / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism; D008236:Lypressin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000819:agonists*; D000077585:Terlipressin; D014162:Transfection / Q000379:methods; D014667:Vasopressins / Q000187:drug effects / Q000378:metabolism
chemical_list: D007295:Inositol Phosphates; D011355:Prodrugs; D017483:Receptors, Vasopressin; D014667:Vasopressins; D008236:Lypressin; D000077585:Terlipressin; D000242:Cyclic AMP
keywords: Hepatorenal syndrome; SR49059, PubChem CID: 60943; Terlipressin; Terlipressin, PubChem CID: 72081; V1A receptor; V2 receptor; Vasopressin receptors; [Arginine(8)]Vasopressin, PubChem CID: 90488786; [Lysine(8)]Vasopressin, PubChem CID: 90488785