Attenuation of central alpha 2 adrenergic action in diabetic rats.
Molecular components in transmembrane signaling may be dysfunctional in insulin-deficient states. To investigate whether the alpha 2 adrenergic receptor-effector mechanism is functionally altered by insulin deficiency, we determined the hypnotic response to dexmedetomidine [(+)4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, a highly-selective alpha 2 agonist, in streptozotocin-induced diabetic rats. The duration of the loss of righting reflex (sleep time) in response to dexmedetomidine, 0.25 mg.kg-1 IP, was measured in rats pretreated with streptozotocin, 50 mg.kg-1 IP. Dexmedetomidine sleep time was significantly shortened when tested 10 days (-25%), 3 (-29%), 6 (-35%) and 8 (-47%) weeks into the diabetic state. Supplementation of the diabetic rats with insulin normalized alpha 2 responsiveness. Acute hyperglycemia did not reduce dexmedetomidine-induced sleep time. Sleep time was also reduced when dexmedetomidine was administered via the intracerebroventricular (ICV) route at 4 (-21%) and 8 (-29%) weeks after streptozotocin. Thus the central nervous system response to the alpha 2 adrenergic agonist has become attenuated. The mechanism may involve a perturbation of an insulin-sensitive molecular component of the signal transduction pathway responsible for alpha 2 adrenoceptor-mediated anesthetic action.
Department of Anesthesia, Stanford University School of Medicine, CA 94305.
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D020926:Medetomidine; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D001786:Blood Glucose; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D010566:Virulence Factors, Bordetella; D019204:GTP-Binding Proteins; D020926:Medetomidine