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Dexmedetomidine (DEX), a highly selective agonist of α 2 -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  h ). In this study, addition of DEX to pituitary GH 3 cells caused a time- and concentration-dependent reduction in the amplitude of I  h with an IC 50 value of 1.21 μM and a K  D value of 1.97 μM. A hyperpolarizing shift in the activation curve of I  h by 10 mV was observed in the presence of DEX. The voltage-dependent hysteresis of I  h 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 I  h , while subsequent addition of yohimbine (10 μM) did not attenuate the inhibitory effect on I  h 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 I  h 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  h 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.

international journal of molecular sciences

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