Telmisartan, an Antagonist of Angiotensin II Receptors, Accentuates Voltage-Gated Na+ Currents and Hippocampal Neuronal Excitability

Abstract

Telmisartan (TEL), a non-peptide blocker of the angiotensin II type 1 receptor, is a widely used antihypertensive agent. Nevertheless, its neuronal ionic effects and how they potentially affect neuronal network excitability remain largely unclear. With the aid of patch-clamp technology, the effects of TEL on membrane ion currents present in hippocampal neurons (mHippoE-14 cells) were investigated. For additional characterization of the effects of TEL on hippocampal neuronal excitability, we undertook in vivo studies on Sprague Dawley (SD) rats using pilocarpine-induced seizure modeling, a hippocampal histopathological analysis, and inhibitory avoidance testing. In these hippocampal neurons, TEL increased the peak amplitude of I Na , with a concomitant decline in the current inactivation rate. The TEL concentration dependently enhanced the peak amplitude of depolarization-elicited I Na and lessened the inactivation rate of I Na. By comparison, TEL was more efficacious in stimulating the peak I Na and in prolonging the inactivation time course of this current than tefluthrin or (-)-epicatechin-3-gallate. In the continued presence of pioglitazone, the TEL-perturbed stimulation of I Na remained effective. In addition, cell exposure to TEL shifted the steady-state inactivation I Na curve to fewer negative potentials with no perturbations of the slope factor. Unlike chlorotoxin, either ranolazine, eugenol, or KMUP-1 reversed TEL-mediated increases in the strength of non-inactivating I Na. In the cell-attached voltage-clamp recordings, TEL shortened the latency in the generation of action currents. Meanwhile, TEL increased the peak I Na , with a concurrent decrease in current inactivation in HEKT293T cells expressing SCN5A. Furthermore, although TEL did not aggravate pilocarpine-induced chronic seizures and tended to preserve cognitive performance, it significantly accentuated hippocampal mossy fiber sprouting. Collectively, TEL stimulation of peak I Na in combination with an apparent retardation in current inactivation could be an important mechanism through which hippocampal neuronal excitability is increased, and hippocampal network excitability is accentuated following status epilepticus, suggesting further attention to this finding.

The Integrated Effects of Brivaracetam, a Selective Analog of Levetiracetam, on Ionic Currents and Neuronal Excitability

“…In both of the OD-1 and lithium-pilocarpine groups, the seizure characteristics of the rats during acute seizures were similar to those reported elsewhere [ 51 , 55 , 56 ]. The seizures were scored using the Racine scale [ 56 ].…”

“…The seizures were scored using the Racine scale [ 56 ]. The rats were given zoletil (50 mg/kg, ip), xylazine (20 mg, ip), and atropine (0.2 mg/kg, sc) to diminish the seizures if their status epilepticus lasted for 20 min [ 51 , 55 , 56 , 57 , 58 ]. Mortality was calculated during the first 24 h after seizure onset.…”

“…The pituitary adenomatous cell line, GH 3 , was acquired from the Bioresource Collection and Research Center (BCRC-60015, http://catalog.bcrc.firdi.org.tw/BcrcContent? bid=60015 (accessed on 26 March 2021), Hsinchu, Taiwan) [49], and the embryonic mouse hippocampal cell line, mHippoE-14, was obtained from Cedarlane CELLutions Biosystems Inc. (Hycell International Co., Taipei, Taiwan) [50,51]. The GH 3 cells were maintained in Ham's F-12 medium supplemented with 2.5% fetal bovine serum (v/v), 15% horse serum (v/v), and 2 mM L-glutamine, and the mHippoE-14 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (v/v) and 2 mM L-glutamine.…”

Characterization of Direct Perturbations on Voltage-Gated Sodium Current by Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker

“…There are nine isoforms (i.e., Na V 1.1–1.9 [or SCN1A-SCN5A and SCN8A-SCN11A]) which are expressed in mammalian excitable tissues, including endocrine system [ 19 , 20 ]. Of notice, several inhibitors have been previously described to preferentially block the late component of voltage-gated Na + current ( I Na ), such as ranolazine (Ran) and KMUP-1 [ 21 , 22 ], while some of Na V -channel activators (e.g., pyrethroids and telmisartan) have been reported in different types of excitable cells [ 23 , 24 , 25 , 26 ]. As an endocrine-disrupting agent, tefluthrin or cypermethrin is, respectively, type I or II pyrethroid known to activate I Na [ 23 , 25 , 27 ].…”

The Evidence for Sparsentan-Mediated Inhibition of INa and IK(erg): Possibly Unlinked to Its Antagonism of Angiotensin II or Endothelin Type a Receptor

“…Sparsentan has been previously demonstrated to be a dual antagonist of endothelin type A (ET A ) and angiotensin II (AngII) receptors [ 2 , 3 , 4 , 34 ]. The activity of ET A or AngII receptors has been reported to be abundantly distributed in pituitary cells [ 15 , 18 , 35 , 36 ].…”