Abstract
In the rat, oxytocin (OT) produces dose-dependent diuretic and natriuretic responses. Post-translational enzymatic conversion of the OT biosynthetic precursor forms both mature and C-terminally extended peptides. The plasma concentrations of these C-terminally extended peptides (OT-G; OT-GK and OT-GKR) are elevated in newborns and pregnant rats. Intravenous injection of OT-GKR to rats inhibits diuresis, whereas injection of amidated OT stimulates diuresis. Since OT and OT-GKR show different effects on the urine flow, we investigated whether OT-GKR modulates renal action by inhibition of the arginine-vasopressin (AVP) receptor V2 (V2R), the receptor involved in renal water reabsorption. Experiments were carried out in the 8-week-old Wistar rats receiving intravenous (iv) injections of vehicle, OT, OT-GKR or OT+OT-GKR combination. OT (10 μmol/kg) increased urine outflow by 40% (P<0.01) and sodium excretion by 47% (P<0.01). Treatment with OT-GKR (10 μmol/kg) decreased diuresis by 50% (P<0.001), decreased sodium excretion by 50% (P<0.05) and lowered potassium by 42% (P<0.05). OT antagonist (OTA) reduced diuresis and natriuresis exerted by OT, whereas the anti-diuretic effect of OT-GKR was unaffected by OTA. The treatment with V2R antagonist (V2A) in the presence and absence of OT induced diuresis, sodium and potassium outflow. V2A in the presence of OT-GKR only partially increased diuresis and natriuresis. Autoradiography and molecular docking analysis showed potent binding of OT-GKR to V2R. Finally, the release of cAMP from CHO cells overexpressing V2 receptor was induced by low concentration of AVP (EC50:4.2e-011), at higher concentrations of OT (EC50:3.2e-010) and by the highest concentrations of OT-GKR (EC50:1.1e-006). OT-GKR potentiated cAMP release when combined with AVP, but blocked cAMP release when combined with OT. These results suggest that OT-GKR by competing for the OT renal receptor (OTR) and binding to V2R in the kidney, induces anti-diuretic, anti-natriuretic, and anti-kaliuretic effects.
Highlights
It is well-established that oxytocin (OT) plays a critical role in reproductive function, including parturition and lactation [1]
OT and arginine vasopressin (AVP, antidiuretic hormone) are nonapeptides synthesized by the hypothalamus and these neuropeptides are structurally similar in amino acid composition and sequence, they fundamentally act on different receptors for physiological function [1, 3]
Specific [3H]OT binding to glomeruli was demonstrated by autoradiography and the presence of OT is currently known (OTR) on glomerular structures may suggest the involvement of OT on renal hemodynamics, including the effects primarily attributed to AVP [4]
Summary
It is well-established that oxytocin (OT) plays a critical role in reproductive function, including parturition and lactation [1]. OT and arginine vasopressin (AVP, antidiuretic hormone) are nonapeptides synthesized by the hypothalamus and these neuropeptides are structurally similar in amino acid composition and sequence, they fundamentally act on different receptors for physiological function [1, 3]. Specific [3H]OT binding to glomeruli was demonstrated by autoradiography and the presence of OTR on glomerular structures may suggest the involvement of OT on renal hemodynamics, including the effects primarily attributed to AVP [4]. Depending on the concentration and route of administration, OT evokes both diuretic and antidiuretic responses in the rat [5]. At pharmacological concentrations [9, 10] or in the response to chronic OT infusions, the antidiuretic effect of OT has been suggested to occur by binding to the V2 receptor (V2R)
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