Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile. (November 2016)

• Record Type: Journal Article
• Authors: Colson, Pascal H.; Virsolvy, Anne; Gaudard, Philippe; Charrabi, Azzouz; Corbani, Maithé; Manière, Maxime J.; Richard, Sylvain; Guillon, Gilles
• Is Part Of: Pharmacological research. Volume 113(2016:Nov.)Part A
• Page Start: 257
• Page End: 264
• Publication Date: 2016-11
• Subjects: Terlipressin, PubChem CID: 72081 -- [Arginine8]Vasopressin, PubChem CID: 90488786 -- [Lysine8]Vasopressin, PubChem CID: 90488785 -- SR49059, PubChem CID: 60943; AVP [arginine8]vasopressin -- LVP [lysine8]vasopressin -- HRS hepatorenal syndrome -- VSMCs vascular smooth muscle cells -- hV1A-R, hV1B-R and hV2-R human V1A V1B and V2 vasopressin receptor -- BSA bovine serum albumin -- PLC phospholipase C -- IPs total inositol lipids -- AC adenylate cyclase -- ATP adenosyl triphospshate -- cAMP cyclic adenosyl monophosphate -- [Ca2+]I cytosolic Ca2+ -- Ki affinity constant of peptide -- Kact concentration of peptide leading to half maximal stimulation -- Emax peptide maximal efficiency; V1A receptor -- V2 receptor -- Vasopressin receptors -- Hepatorenal syndrome -- Terlipressin; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.08.027
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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 lysine 8 -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. Conclusions: 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.