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

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 [(3)H]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.