In Reply:-I thank Drs. Haddad, Johns, and Pajewski for their interest and valuable comments regarding our recent article. [1] I have to admit that our speculation regarding the role of cyclic guanosine monophosphate (cGMP) in the mechanism of sevoflurane minimum alveolar concentration (MAC) reduction is based on rather weak evidence. I also agree with Haddad et al. regarding the possible development of compensatory mechanisms as we described in our discussion. However, we would like to point out that, although we found a correlation between the reduction of cGMP and sevoflurane MAC after acute 7-NI, there was a marked difference in the magnitude of reduction of the two parameters. Together with the dissociation of the two parameters after long-term 7-NI administration, these observations may suggest that the relation between cGMP and MAC is not linear. It is conceivable that only a small amount of nitric oxide or cGMP, or both, is necessary to maintain normal nociception. If this is the case, variation of nitric oxide synthase (NOS) activity or cGMP concentrations, or both, in the brain may not closely correlate with MAC of volatile anesthetics. I would also like to point out the limitation of the studies of our own [1] and others [2] that tested the effects of NOS inhibitors on anesthetic potencies and NOS activities. In two studies in which cGMP or NOS activity, or both, were measured after NOS inhibitor administration, cGMP concentration and NOS activity were not (and could not be) measured during tail pinch, but were measured in the cerebellum of unstimulated animals that had received the same dose of NOS inhibitors as those that had tail pinch. [1,2] Therefore, although cerebellar cGMP concentration and NOS activity should reflect those in the spinal cord (proposed nociceptive pathway in tail pinch, see discussion of Ichinose et al. [1]), [3] no data are available regarding NOS activity or cGMP concentrations during MAC measurements (tail pinch).

Fumito Ichinose, M.D.

Department of Anesthesia and Critical Care; Massachusetts General Hospital; Boston, Massachusetts 02114;

(Accepted for publication December 4, 1998.)

Ichinose F, Mi W, Miyazaki M, Onouchi T, Goto T, Morita S: Lack of correlation between the reduction of sevoflurane MAC and the cerebellar cyclic GMP concentrations in mice treated with 7-nitroindazole. Anesthesiology 1998; 89:143-8
Adachi T, Shinomura T, Nakao S, Kurata J, Murakawa M, Shichino T, Seo N, Mori K: Chronic treatment with nitric oxide synthase (NOS) inhibitor profoundly reduces cerebellar NOS activity and cyclic guanosine monophosphate but does not modify minimum alveolar anesthetic concentration. Anesth Analg 1995; 81:862-5
Gaffen Z, Bland-Ward PA, Pitcher A, Wallace P, Moore PK: Augmented antinociception following 7-nitro indazole and flurbiprofen in the conscious mouse. Eur J Pharmacol 1994; 271:445-52