In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V₁ and V₂

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V₁) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys₈]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg₈]-vasopressin (AVP) at V₁ and vasopressin-2 (V₂) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V₁ and V₂ receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [³H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V₁) and cyclic adenosine monophosphate (V₂). Binding potency at V₁ and V₂ was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V₁ than for V₂. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V₁ and a full agonist at V₂; LVP was a full agonist at both V₁ and V₂. The in vivo response to terlipressin is likely due to the partial V₁ agonist activity of terlipressin and full V₁ agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.