Inhibition of nitric oxide metabolism enhances the hypnotic-anesthetic action of the alpha2-adrenoceptor agonist dexmedetomidine in vivo.
Nitric oxide (NO) synthase inhibitors have been demonstrated to increase the anesthetic action of volatile and intravenous anesthetics. This study was designed to test the hypothesis that, comparable to other general anesthetics, the hypnotic-anesthetic action of dexmedetomidine is increased after administration of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). With approval of the local animal care committee, the anesthetic potency of dexmedetomidine or a combination of dexmedetomidine plus 1 mM L-NAME was determined in Xenopus laevis larvae. Anesthesia was defined as loss of righting reflex. Concentration-response curves were calculated by a logistic approach. Additional experiments were performed that exposed the animals to dexmedetomidine in the presence of L-NAME plus L-arginine, as well as D-NAME. In the dexmedetomidine and the dexmedetomidine plus L-NAME groups, the fraction of anesthetized animals increased with increasing concentrations of dexmedetomidine. Calculation of the half-maximal effective concentration (EC50) resulted in a value of 7.8+/-0.6 microM for dexmedetomidine and 3.8+/-0.2 microM for dexmedetomidine plus L-NAME (p<0.05). Addition of L-arginine reversed the potentiating effect of L-NAME. Administration of D-NAME did not affect the EC50 of dexmedetomidine. In a manner comparable to that of other general anesthetics, the anesthetic effect of dexmedetomidine was increased by about 51% by an acute inhibition of the NO metabolism. Together with recent findings that alpha2-adrenoceptor agonists decrease the NO mediated synthesis of cGMP similar to volatile and intravenous anesthetics, the results suggest that the NO/cGMP pathway is an important mediator of the anesthetic action of these compounds.
Tonner
P H
PH
Department of Anaesthesiology, University Hospital Eppendorf, Hamburg, Germany.
Scholz
J
J
Schlamp
N
N
Schulte am Esch
J
J
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018681:Anesthetics, General / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007814:Larva; D020926:Medetomidine; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D014982:Xenopus laevis
D000316:Adrenergic alpha-Agonists; D018681:Anesthetics, General; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D009569:Nitric Oxide; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D020926:Medetomidine; D019331:NG-Nitroarginine Methyl Ester