Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on α2-Adrenergic Receptors.

Te-Ling Lu,Sheng-Nan Wu,Te-Jung Lu

doi:10.3390/ijms21239110

Abstract

Dexmedetomidine (DEX), a highly selective agonist of α2-adrenergic receptors, has been tailored for sedation without risk of respiratory depression. Our hypothesis is that DEX produces any direct perturbations on ionic currents (e.g., hyperpolarization-activated cation current, Ih). In this study, addition of DEX to pituitary GH3 cells caused a time- and concentration-dependent reduction in the amplitude of Ih with an IC50 value of 1.21 μM and a KD value of 1.97 μM. A hyperpolarizing shift in the activation curve of Ih by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of Ih elicited by long-lasting triangular ramp pulse was also dose-dependently reduced during its presence. In continued presence of DEX (1 μM), further addition of OXAL (10 μM) or replacement with high K+ could reverse DEX-mediated inhibition of Ih, while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on Ih amplitude. The addition of 3 μM DEX mildly suppressed the amplitude of erg-mediated K+ current. Under current-clamp potential recordings, the exposure to DEX could diminish the firing frequency of spontaneous action potentials. In pheochromocytoma PC12 cells, DEX was effective at suppressing Ih together with a slowing in activation time course of the current. Taken together, findings from this study strongly suggest that during cell exposure to DEX used at clinically relevant concentrations, the DEX-mediated block of Ih appears to be direct and would particularly be one of the ionic mechanisms underlying reduced membrane excitability in the in vivo endocrine or neuroendocrine cells.

Highlights

Dexmedetomidine (DEX, (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, Precedex®), a lipophilic imidiazole derivative, is regarded as a potent and selective agonist of the α2-adrenergic receptors [1]
Findings from the present study are as follows: (a) in pituitary GH3 cells, DEX produced a depressant action on Ih in a concentration- and state-dependent fashion with an IC50 or KD values of 1.21 or 1.97 μM, respectively; (b) the presence of DEX shifted the steady-state activation curve of Ih along the voltage axis to more hyperpolarized potential; (c) this agent was capable of diminishing the voltage-dependent hysteresis of Ih during long-lasting triangular ramp pulse, (d) it mildly suppressed deactivating IK(erg), (e) it diminished the firing frequency of spontaneous action potential (AP) detected under current-clamp conditions, and (f) in pheochromocytoma PC12 cells, this drug suppressed Ih effectively
These are important observations, because DEX-induced block of Ih shown can be a potential ionic mechanism through which it may be efficacious in depressing intrinsic membrane excitability of neurons, or neuroendocrine or endocrine cells in vivo

Summary

Introduction

Dexmedetomidine (DEX, (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, Precedex®), a lipophilic imidiazole derivative, is regarded as a potent and selective agonist of the α2-adrenergic receptors [1]. A recent report showed that guanabenz, another α2-adrenoceptor agonist, could directly suppress hyperpolarization-activated cation current in mesencephalic trigeminal nucleus neurons [5]. DEX at high concentrations was previously reported to suppress compound action potentials in frog sciatic nerve, and this action is thought to be independent on its activation of the α2-adrenergic receptor [4]. DEX was shown to increase the expression of phosphorylated ERK1 and 2 in the hippocampus, a key element in signal transduction, and this action was independent from its binding to the α2-adrenerginic receptor [6]

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Conclusion