NITRIC-OXIDE SYNTHASE INHIBITOR DOSE-DEPENDENTLY AND REVERSIBLY REDUCES THE THRESHOLD FOR HALOTHANE ANESTHESIA - A ROLE FOR NITRIC-OXIDE IN MEDIATING CONSCIOUSNESS

Nitric oxide is a newly recognized cell messenger for the activation of soluble guanylate cyclase and is produced from L-arginine by the enzyme nitric oxide synthase in a wide variety of tissues, including vascular endothelium and brain. Inhalational anesthetics inhibit nitric oxide production from vascular endothelium and also decrease resting cyclic guanosine monophosphate content in multiple brain regions. Halothane has been shown to depress neurotransmission by L-glutamate and N-methyl-D-aspartate. These amino acid neurotransmitters are known to increase neuronal cyclic guanosine monophosphate content by stimulation of nitric oxide production. To investigate the possible involvement of the L-arginine-to-nitric oxide pathway in the anesthetic state, the effect of a specific nitric oxide synthase inhibitor, nitro(G)-L-arginine methyl ester, on the minimum alveolar concentration (MAC) for halothane anesthesia was determined in Sprague-Dawley rats. Bolus injection of nitro(G)-L-arginine methyl ester at 0, 1, 5, 10, 20, and 30 mg/kg resulted in a dose-dependent reduction in MAC for halothane of 0 +/- 0, 2.3 +/- 0.4, 21.5 +/- 3.9, 30.5 +/- 2.4, 51.0 +/- 7.8, and 26.0 +/- 2.8%, respectively. Nitro(G)-L-arginine methyl ester had no effect on MAC for halothane. Bolus infusion of L-arginine 300 mg/kg after MAC reduction by nitro(G)-L-arginine methyl ester 10 mg/kg resulted in an immediate and complete reversal of the MAC reduction. No reversal was observed after infusion of D-arginine 300 mg/kg. MAC reduction by nitro(G)-L-arginine methyl ester 1, 5, 10, 20 and 30 mg/kg was accompanied by an increase in systolic blood pressure (1 +/- 3, 29 +/- 6, 27 +/- 3, 45 +/- 3, and 27 +/- 5% respectively) and diastolic blood pressure (1 +/- 6, 30 +/- 6, 29 +/- 7, 53 +/- 2, and 29 7% respectively), and a small decrease in heart rate (-2 +/- 3, -8 +/- 4, -11 +/- 2, -5 +/- 8, and -15 +/- 3%, respectively). This dose-dependent and reversible decrease in MAC by nitro(G)-L-arginine methyl ester suggests that inhibition of the nitric oxide pathway decreases the level of consciousness and augments anesthesia, analgesia, or sedation.