Inhibition of nitric oxide metabolism enhances the hypnotic-anesthetic action of the alpha(2)-adrenoceptor agonist dexmedetomidine in vivo

Nitric oxide (NO) synthase inhibitors have been demonstrated to increase th e anesthetic action of volatile and intravenous anesthetics. This study was designed to test the hypothesis that, comparable to other general anesthet ics, the hypnotic-anesthetic action of dexmedetomidine is increased after a dministration 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 d etermined in Xenopus laevis larvae. Anesthesia was defined as loss of right ing reflex. Concentration-response curves were calculated by a logistic app roach. Additional experiments were pet-formed that exposed the animals to d exmedetomidine 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 frac tion of anesthetized animals increased with increasing concentrations of de xmedetomidine. Calculation of the half-maximal effective concentration (EC5 0) resulted in a value of 7.8 +/- 0.6 mu M for dexmedetomidine and 3.8 +/- 0.2 mu M for dexmedetomidine plus L-NAME (p<0.05), Addition of L-arginine r eversed 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 inhibitio n of the NO metabolism. Together with recent findings that alpha(2)-adrenoc eptor agonists decrease the NO mediated synthesis of cGMP similar to volati le and intravenous anesthetics, the results suggest that the NO/cGMP pathwa y is an important mediator of the anesthetic action of these compounds.