Abstract
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.