Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monitoring of extracellular cGMP during intracerebral microdialysis in freely moving rats permits the study of the functional changes occurring in the glutamate receptor/nitric oxide (NO) synthase/guanylyl cyclase pathway and the relationship of these changes to animal behaviour. When infused into the rat hippocampus in Mg2+-free medium, cyclothiazide, a blocker of desensitization of the AMPA-preferring receptor, increased cGMP levels. The effect of cyclothiazide (300 microM) was abolished by the NO synthase inhibitor L-NARG (100 microM) or the soluble guanylyl cyclase inhibitor ODQ (100 microM). During cyclothiazide infusion the animals displayed a pre-convulsive behaviour characterized by frequent "wet dog shakes" (WDS). Neither L-NARG nor ODQ decreased the WDS episodes. Both cGMP and WDS responses elicited by cyclothiazide were prevented by blocking NMDA receptor function with the glutamate site antagonist CGS 19755 (100 microM), the channel antagonist MK-801 (30 microM) or Mg2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 microM) and NBQX (100 microM) abolished the WDS episodes but could not inhibit the cyclothiazide-evoked cGMP response. DNQX or NBQX (but not MK-801) elevated, on their own, extracellular cGMP levels. The cGMP response elicited by the antagonists appears to be due to prevention of a glutamate-dependent inhibitory GABAergic tone, since infusion of bicuculline (50 microM) caused a strong cGMP response. The results suggest that (a) AMPA/kainate receptors linked to the NO/cGMP pathway in the hippocampus (but not NMDA receptors) are tonically activated and kept in a desensitized state by endogenous glutamate; (b) blockade of AMPA/kainate receptor desensitization by cyclothiazide leads to endogenous activation of NMDA receptors; (c) the hippocampal NO/cGMP system is under a GABAergic inhibitory tone driven by non-NMDA ionotropic receptors; (d) the pre-convulsive episodes observed depend on hippocampal NMDA receptor activation but not on NO and cGMP production.
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PMID:The glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats: modulation by cyclothiazide, interaction with GABA and the behavioural consequences. 942 27

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.
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PMID:In vivo microdialysis study of GABA(A) and GABA(B) receptors modulating the glutamate receptor/NO/cyclic GMP pathway in the rat hippocampus. 942 28

In a previous study, we reported depressor and bradycardiac responses after L-glutamate (L-glu) microinjection into the diagonal band of Broca (dbB) in anesthetized rats. Here, we report the glutamatergic-receptor subtype mediating the cardiovascular effects evoked by L-glu injection into the dbB and the involvement of local nitric oxide (NO) mechanisms as well as peripheral effectors. Microinjections of 100 nL of L-glu (1, 27, 81, 130 or 200 nmol) into the dbB of urethane-anesthetized rats caused short-lasting depressor and bradycardiac responses. Responses were dose-related, with an ED(50) of approximately 81 nmol. This dose was used in later experiments. The cardiovascular responses to L-glu in the dbB were abolished by local pretreatment (100 nL) with the selective N-methyl-D-aspartic acid (NMDA) receptor antagonist LY235959 (4 nmol) but were not affected by pretreatment with the selective non-NMDA receptor antagonist NBQX (4 nmol). Responses to L-glu in the dbB were blocked by local pretreatment with the selective neuronal NO-synthase (nNOS) inhibitor N(omega)-propyl-L-arginine (NPLA, 0.04 nmol); the NO scavenger carboxy-PTIO (C-PTIO, 1 nmol) or the guanylate cyclase inhibitor ODQ (1 nmol). These results suggest that the microinjection of L-glu into the dbB of urethane-anesthetized rats causes dose-related depressor and bradycardiac responses through the NMDA receptor-NO-guanylate cyclase pathway.
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PMID:Interaction between glutamatergic and nitrergic mechanisms mediating cardiovascular responses to L-glutamate injection in the diagonal band of Broca in anesthetized rats. 1776 Nov 99