title: Anesthetic profile of dexmedetomidine identified by stimulus-response and continuous measurements in rats.
abstract: This study characterizes the anesthetic profile of dexmedetomidine on the basis of steady-state plasma concentrations using defined stimulus-response, ventilatory, and continuous electroencephalographic (EEG) and cardiovascular effect measures in rats. At constant plasma concentrations of dexmedetomidine (range, 0.5-19 ng/ml), targeted and maintained by target-controlled infusion, the whisker reflex, righting reflex, startle reflex (to noise), tail clamp response, hot water tail-flick latency, and attenuation of heart rate (HR) increase associated with tail-flick (sympathoadrenal block) and corneal reflex, were assessed in 22 rats. EEG (power in 0.5- to 3.5-Hz frequency band), mean arterial pressure, and HR were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The following steady-state plasma EC(50) values of dexmedetomidine (mean +/- S.E. nanograms per milliliter) were estimated: HR decrease (0.51 +/- 0.04), EEG (1.02 +/- 0.08), whisker reflex (1.09 +/- 0.10), sympathoadrenal block (1.85 +/- 0.80), mean arterial blood pressure increase (1.99 +/- 0.44), righting reflex (2.13 +/- 0.15), tail-flick latency (3.65 +/- 0.87), startle reflex (3.75 +/- 0.64), tail clamp (5.49 +/- 1.34), and corneal reflex (24.5 +/- 12.3). At the EC(50) value of tail clamp, ventilatory depression was minor. In rats, dexmedetomidine creates bradycardia, sedation/hypnosis, sympathoadrenal blocking effects, and blood pressure-increasing effects at plasma concentrations below 2.5 ng/ml. Higher plasma concentrations are needed to loose the startle reflex, tail-flick, tail clamp, and corneal reflex responses. Ventilatory depressant effects are minor. The applied EEG measure seems to reflect sedation/hypnosis but seems to have limited value to predict the deeper levels of analgesia and anesthesia of dexmedetomidine.
authors.affiliation: Department of Anesthesia and Pharmacology, Stanford University School of Medicine, Stanford, California. kbol@janbe.jnj.com
authors.forename: C J
authors.initials: CJ
authors.lastname: Bol
authors.forename: J P
authors.initials: JP
authors.lastname: Vogelaar
authors.forename: J W
authors.initials: JW
authors.lastname: Mandema
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018712:Analgesics, Non-Narcotic; D007093:Imidazoles; D020926:Medetomidine