A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia

Abstract

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-dependent Mechanism

“…administration, but this effect lasted for at least 6 h, as opposed to 45 min for the effects of i. v.administration in normotensive animals. These results are in line with the prolonged in vivo half-life of LIT01-196 (156 min) in the bloodstream after s.c. administration in normotensive rats as previously reported ( Flahault et al, 2021 ).…”

“…These results are in line with the previously reported in vivo LIT01-196 half-life of 28 min in the bloodstream, versus 50 s for K17F, in SD male rats after i.v. administration ( Flahault et al, 2021 ). The LIT01-196-induced BP decrease does not result from the action of the compound at the brain level since LIT01-196 was previously shown not to cross the blood-brain barrier and enter the brain after systemic administration to control rats ( Flahault et al, 2021 ).…”

“…administration ( Flahault et al, 2021 ). The LIT01-196-induced BP decrease does not result from the action of the compound at the brain level since LIT01-196 was previously shown not to cross the blood-brain barrier and enter the brain after systemic administration to control rats ( Flahault et al, 2021 ). Other metabolically stable apelin analogs have been developed to increase the half-life of the peptide and its in vivo activity.…”

“…injection of K17F has been shown to increase aqueous diuresis in anesthetized lactating female rats ( Hus-Citharel et al, 2008 ), and LIT01-196 given by i.v. or s.c. route in control rats increases urine output and decreases urine osmolality ( Flahault et al, 2021 ). We therefore evaluated the effects of LIT01-196 administration on diuresis and urinary sodium excretion in hypertensive DOCA-salt rats after 4 days of treatment.…”

“…This chemical modification increased the in vivo half-life of LIT01-196 in the bloodstream to 28 min after i.v. and 156 min after subcutaneous (s.c.) administrations in conscious rats ( Flahault et al, 2021 ) without altering its pharmacological properties in terms of the affinity for the ApelinR, inhibition of cAMP production, ApelinR internalization, ß-arrestin-2 recruitment and ERK phosphorylation ( Gerbier et al, 2017 ). Like K17F, LIT01-196 induced a NO-dependent vasorelaxation of rat aorta pre-contracted with norepinephrine and rat glomerular arterioles pre-contracted with angiotensin II ( Gerbier et al, 2017 ).…”