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.
CONCLUSIONS: