title: Regulation of cyclic GMP levels in the rat frontal cortex in vivo: effects of exogenous carbon monoxide and phosphodiesterase inhibition.
abstract: 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 nitric oxide (NO), and effects of exogenous carbon monoxide (CO) and phosphodiesterase activity, as possible regulators of cortical CGMP levels. Perfusion with CO-saturated aCSF (approximately 1 mM CO) failed to significantly stimulate cortical cGMP levels. For comparison, cerebellar cGMP levels increased by 2-fold during CO stimulation, followed by a prolonged response that was fully reversible with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Cortical perfusion with zinc protopophyrin-IX (100 microM), a widely used inhibitor of the CO-generating enzyme heme oxygenase, suppressed cGMP levels by 50%, a response that spontaneously recovered in spite of the continuous presence of the metalloporphyrin. Perfusion with isobutylmethyl xanthine IBMX (1 mM) resulted in 5-fold increase in cortical cGMP levels, as compared to basal levels without IBMX. In the presence of IBMX, L-NAME suppressed basal cortical cGMP levels by 70% indicating that NO synthase activity generates the bulk of cGMP in this brain region, as previously shown for basal cGMP production in the hippocampus and the cerebellum. These data also emphasize a crucial role for phosphodiesterase activity 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kuopio, Finland.
authors.forename: K S
authors.initials: KS
authors.lastname: Laitinen
authors.forename: K
authors.initials: K
authors.lastname: Salovaara
authors.forename: S
authors.initials: S
authors.lastname: Severgnini
authors.forename: J T
authors.initials: JT
authors.lastname: Laitinen
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine; D019331:NG-Nitroarginine Methyl Ester