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2017 ; 21
(9
): 1767-1780
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The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2
trafficking and function: an in vitro and in vivo assessment
#MMPMID28326667
Tamma G
; Di Mise A
; Ranieri M
; Geller A
; Tamma R
; Zallone A
; Valenti G
J Cell Mol Med
2017[Sep]; 21
(9
): 1767-1780
PMID28326667
show ga
Tolvaptan, a selective vasopressin V2 receptor antagonist, is a new generation
diuretic. Its clinical efficacy is in principle due to impaired
vasopressin-regulated water reabsorption via aquaporin-2 (AQP2). Nevertheless, no
direct in vitro evidence that tolvaptan prevents AQP2-mediated water transport,
nor that this pathway is targeted in vivo in patients with syndrome of
inappropriate antidiuresis (SIAD) has been provided. The effects of tolvaptan on
the vasopressin-cAMP/PKA signalling cascade were investigated in MDCK cells
expressing endogenous V2R and in mouse kidney. In MDCK, tolvaptan prevented
dDAVP-induced increase in ser256-AQP2 and osmotic water permeability. A similar
effect on ser256-AQP2 was found in V1aR -/- mice, thus confirming the V2R
selectively. Of note, calcium calibration in MDCK showed that tolvaptan per se
caused calcium mobilization from the endoplasmic reticulum resulting in a
significant increase in basal intracellular calcium. This effect was only
observed in cells expressing the V2R, indicating that it requires the
tolvaptan-V2R interaction. Consistent with this finding, tolvaptan partially
reduced the increase in ser256-AQP2 and the water permeability in response to
forskolin, a direct activator of adenylyl cyclase (AC), suggesting that the
increase in intracellular calcium is associated with an inhibition of the
calcium-inhibitable AC type VI. Furthermore, tolvaptan treatment reduced AQP2
excretion in two SIAD patients and normalized plasma sodium concentration. These
data represent the first detailed demonstration of the central role of AQP2
blockade in the aquaretic effect of tolvaptan and underscore a novel effect in
raising intracellular calcium that can be of significant clinical relevance.
|Aged, 80 and over
[MESH]
|Animals
[MESH]
|Antidiuretic Hormone Receptor Antagonists/*pharmacology/therapeutic use
[MESH]