Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on α<sub>2</sub>-Adrenergic Receptors
Dexmedetomidine (DEX), a highly selective agonist of α<sub>2</sub>-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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/23/9110 |
| Summary: | Dexmedetomidine (DEX), a highly selective agonist of α<sub>2</sub>-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, <i>I</i><sub>h</sub>). In this study, addition of DEX to pituitary GH<sub>3</sub> cells caused a time- and concentration-dependent reduction in the amplitude of <i>I</i><sub>h</sub> with an IC<sub>50</sub> value of 1.21 μM and a <i>K</i><sub>D</sub> value of 1.97 μM. A hyperpolarizing shift in the activation curve of <i>I</i><sub>h</sub> by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of <i>I</i><sub>h</sub> 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<sup>+</sup> could reverse DEX-mediated inhibition of <i>I</i><sub>h</sub>, while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on <i>I</i><sub>h</sub> amplitude. The addition of 3 μM DEX mildly suppressed the amplitude of <i>erg</i>-mediated K<sup>+</sup> 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 <i>I</i><sub>h</sub> 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 <i>I</i><sub>h</sub> 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. |
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| ISSN: | 1661-6596 1422-0067 |