In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V ₁ and V ₂

Abstract

Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V ₁) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys ₈]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg ₈]-vasopressin (AVP) at V ₁ and vasopressin-2 (V ₂) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V ₁ and V ₂ 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 (V ₁) and cyclic adenosine monophosphate (V ₂). Binding potency at V ₁ and V ₂ was AVP>LVP>>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V ₁ than for V ₂. Cellular activity potency was also AVP>LVP>>terlipressin. Terlipressin was a partial agonist at V ₁ and a full agonist at V ₂; LVP was a full agonist at both V ₁ and V ₂. The in vivo response to terlipressin is likely due to the partial V ₁ agonist activity of terlipressin and full V ₁ agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.