REGULATION OF CYCLIC-GMP LEVELS IN THE RAT FRONTAL-CORTEX IN-VIVO - EFFECTS OF EXOGENOUS CARBON-MONOXIDE AND PHOSPHODIESTERASE INHIBITION

A microdialysis method combined with a sensitive radioimmunoassay was used to monitor cGMP release in the frontal cortex of the anesthetized rats in vivo. We assessed the relative contribution of endogenous nit ric oxide (NO), and effects of exogenous carbon monoxide (GO) and phos phodiesterase activity, as possible regulators of cortical CGMP levels . Perfusion with GO-saturated aCSF (approximate to 1 mM CO) failed to significantly stimulate cortical cGMP levels. For comparison, cerebell ar cGMP levels increased by 2-fold during CO stimulation, followed by a prolonged response that was fully reversible with the NO synthase in hibitor NG-nitro-L-arginine methyl ester (L-NAME). Cortical perfusion with zinc protopophyrin-IX (100 mu M), a widely used inhibitor of the GO-generating enzyme heme oxygenase, suppressed cGMP levels by 50%, a response that spontaneously recovered in spite of the continuous prese nce of the metalloporphyrin. Perfusion with isobutylmethyl xanthine IB MX (1 mM) resulted in 5-fold increase in cortical cGMP levels, as comp ared to basal levels without IBMX. In the presence of IBMX, L-NAME sup pressed basal cortical cGMP levels by 70% indicating that NO synthase activity generates the bulk of cGMP in this brain region, as previousl y shown for basal cGMP production in the hippocampus and the cerebellu m. These data also emphasize a crucial role for phosphodiesterase acti vity in the maintenance of cGMP levels in vivo in the frontal cortex. The relatively weak responses to exogenous CO lend little support for a role of this gas in regulating basal cortical cGMP levels in vivo.