Abstract
Tolvaptan (TLV), an oral non-peptide antagonist of vasopressin V2 receptor, has been increasingly used for managements in patients with hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion. However, none of the studies have thus far been investigated with regard to its possible perturbations on membrane ion currents in endocrine or neuroendocrine cells. In our electrophysiological study, the whole-cell current recordings showed that the presence of TLV effectively and differentially suppressed the amplitude of delayed rectifier K+ (IK(DR)) and M-type K+ current (IK(M)) in pituitary GH3 cells with an IC50 value of 6.42 and 1.91 μM, respectively. This compound was also capable of shifting the steady-state activation curve of IK(M) to less depolarized potential without any appreciable change in the gating charge of this current. TLV at a concentration greater than 10 μM also suppressed the amplitude of erg-mediated K+ current or the activity of large-conductance Ca2+-activated K+ channels; however, this compound failed to alter the amplitude of hyperpolarization-activated cation current in GH3 cells. In vasopressin-preincubated GH3 cells, TLV-mediated suppression of IK(M) remained little altered. Under current-clamp condition, we also observed that addition of TLV increased the firing of spontaneous action potentials in GH3 cells and further addition of flupirtine could reverse TLV-mediated elevation of the firing. In Madin-Darby canine kidney (MDCK) cells, the K+ current elicited by long ramp pulse was also effectively subject to inhibition by this compound. Findings from the present study were thus stated as saying that the suppression by TLV of multiple type K+ currents could be direct and independent of its antagonism of vasopressin V2 receptors. Our study also reveals an important aspect that should be considered when assessing aquaretic effect of TLV or its structurally similar compounds.
Highlights
Tolvaptan (TLV; Samsca R or Jinarc R ) is recognized as an oral aquaretic agent that functions as a selective, competitive antagonist of vasopressin V2 receptor used to treat hyponatremia associated with congestive heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone (Izumi et al, 2014; Aylwin et al, 2015; Verbalis et al, 2016; Clark et al, 2017; Der-Nigoghossian et al, 2017; Dunlap et al, 2017; Felker et al, 2017; Konstam et al, 2017; Wu et al, 2017a; Berardi et al, 2018; Kogure et al, 2018; Matsukawa et al, 2018; Morris et al, 2018; Oguri et al, 2018a; Sigal et al, 2018; Takimura et al, 2018; Vidic et al, 2019)
Tolvaptan (TLV; Samsca R or Jinarc R, OPC-41061, N-[4-[(7-chloro-2,3,4,5-tetrahydro5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]2-methylbenzamide,C26H25ClN2O3), ivabradine and PD-118057 (2-[[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]amino]benzoic acid) were obtained from Tocris (Union Biomed Inc., Taipei, Taiwan), flupirtine, linopirdine, [Arg8]-vasopressin, nonactin, tetrodotoxin and thyrotropin releasing hormone were from Sigma-Aldrich (St Louis, MO), and pioglitazone was from Takeda Pharmaceuticals (Tokyo, Japan)
Linopirdine is an inhibitor of M-type K+ currents (IK(M))
Summary
Tolvaptan (TLV; Samsca R or Jinarc R ) is recognized as an oral aquaretic agent that functions as a selective, competitive antagonist of vasopressin V2 receptor used to treat hyponatremia associated with congestive heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone (Izumi et al, 2014; Aylwin et al, 2015; Verbalis et al, 2016; Clark et al, 2017; Der-Nigoghossian et al, 2017; Dunlap et al, 2017; Felker et al, 2017; Konstam et al, 2017; Wu et al, 2017a; Berardi et al, 2018; Kogure et al, 2018; Matsukawa et al, 2018; Morris et al, 2018; Oguri et al, 2018a; Sigal et al, 2018; Takimura et al, 2018; Vidic et al, 2019). Voltage-gated K+ (KV) channels play an essential role in determining membrane excitability and the delayed rectifier K+ channels are ubiquitous in endocrine cells. The KV3 subfamily of KV channels is characterized by its biophysical properties exhibiting to have positively shifted voltage dependency and fast deactivation rate. These properties can be expected to limit the Na+ channel, thereby leading to depolarization block and accommodation of repetitive firing at high frequencies (Rudy and McBain, 2001; Tateno and Robinson, 2007). Whether TLV, expected to be a non-peptide vasopressin antagonist, exerts any perturbations on these types of K+ currents (e.g., IK(M) and IK(DR)) or on membrane potential remains largely
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