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

In response to NMDA receptor activation, hippocampal, striatal and cerebellar neurons synthesize nitric oxide (NO), which in turn elevates cGMP levels via guanylate cyclase. NO is increasingly being considered as a transsynaptic retrograde messenger, involved in neuronal plasticity. The effect of an inhibitor of NO synthase, L-NG-nitroarginine (NOArg), was studied on amygdala kindling and on kindled seizures in rats. NOArg increased kindling rate, particularly in its initial period, but did not modify seizure severity in previously kindled rats, although we have no definitive explanation for this effect. However, an enhanced post-synaptic excitability could be attributed to the blockade of the negative feed-back exerted by NO on the NMDA receptor.
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PMID:A nitric oxide (NO) synthase inhibitor accelerates amygdala kindling. 138 71

The role of nitric oxide (NO) in the genesis of motor and electrocortical seizures elicited by administration of excitatory amino acid agonists into the deep prepiriform cortex (DPC) has been evaluated. Motor and electrocortical seizures occurred in rats receiving unilateral microinjections into the DPC of either N-methyl-D-aspartate (NMDA, 5 and 10 nmol) or kainate (KA, 100 pmol). The selective NMDA receptor antagonist 2-amino-7-phosphonoheptanoate (APH), when microinjected into DPC, prevented the development of seizures induced by both NMDA and KA injected in the same site. In addition, methylene blue (20 nmol, which prevents activation of soluble guanylate cyclase) or NG-monomethyl-L-arginine (NMMA, 40 nmol; a specific inhibitor of nitric oxide synthesis), when microinjected into DPC 15 min prior to either NMDA or KA, significantly protected against seizures elicited by both excitatory amino acid agonists. These data confirm the role of excitatory amino acid transmission in the genesis of seizures elicited from the deep prepiriform cortex. They further suggest that activation of excitatory amino acid receptors within the DPC leads to the release of a substance which shares properties with EDRF/NO and contributes to the genesis of seizure activity in this area.
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PMID:Role of nitric oxide in the genesis of excitatory amino acid-induced seizures from the deep prepiriform cortex. 195 95

The objective of the present study was to explore if lesions of the ascending noradrenergic pathways, originating in the locus coeruleus, modulate the cerebral metabolic response to bicuculline-induced seizures in rats. Bilateral noradrenergic lesions were performed by 6-hydroxydopamine injections in the caudal mesencephalon, 12-22 days before seizures were induced in animals ventilated on N2O:O2 (75:25). After 5 min of seizures the brain was frozen in situ and cerebral cortex and hippocampus were sampled for analysis. Labile phosphates, glycolytic metabolites, cyclic nucleotides, and free fatty acids were measured. In another series, lesioned animals were used for measurements of cerebral oxygen consumption. The noradrenergic lesions neither modified the electroencephalographically recorded seizure discharge, nor did they alter cerebral oxygen consumption or cerebral energy state. However, when compared to sham-operated animals, those with noradrenergic lesions had significantly higher (115% and 68%) glycogen concentrations and lower (50% and 52%) cyclic AMP concentrations in cerebral cortex and hippocampus, respectively, demonstrating the marked influence of noradrenergic activity on adenylate cyclase activity and glycogenolysis. The lesions failed to modulate the rise in free fatty acids in the cerebral cortex, or the cyclic GMP concentrations in the cerebral cortex and hippocampus. Thus, increased noradrenergic activity during status epilepticus does not seem responsible for lipolysis or for activation of guanylate cyclase.
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PMID:Influence of lesions of the noradrenergic locus coeruleus system on the cerebral metabolic response to bicuculline-induced seizures. 630 1

Using a reverberatory epilepiform discharge of hippocampal-parahippocampal circuits termed "maximal dentate activation", this study investigated whether the local release of nitric oxide within these circuits functions as an antiepileptic agent. Two nitric oxide synthase inhibitors (L-nitro-arginine methyl ester and 7-nitro-indazole) and a guanylate cyclase inhibitor (methylene blue) were tested, and none had a significant effect on the time to onset or duration of maximal dentate activation. A membrane-permeable analogue of cyclic guanosine monophosphate (cGMP), 8-bromo-cGMP, caused an increase in the time to onset and a decrease in the duration of maximal dentate activation. The number of neurons expressing NADPH diaphorase activity (a marker for nitric oxide synthase) was also examined after repeated elicitation of maximal dentate activation. After 18 seizures there was a significant, but transient, decrease in the number of hilar/subgranular neurons that were NADPH diaphorase-positive. The decrease was only seen at 1 h after the last seizure. There was no induction of NADPH diaphorase activity. These results are not consistent with the hypothesis that, in hippocampal-parahippocampal circuits in vivo, nitric oxide is released in response to neuronal activity and then acts to terminate the neuronal activity.
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PMID:In the hippocampus in vivo, nitric oxide does not appear to function as an endogenous antiepileptic agent. 749 93

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.
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PMID:A new experimental model of epilepsy based on the intraventricular injection of endothelin. 750 66

The role of nitric oxide (NO) in the increase in local cerebral blood flow (LCBF) elicited by focal cortical epileptic seizures was investigated in anesthetized adult rats. Seizures were induced by topical bicuculline methiodide applied through two cranial windows drilled over homotopic sites of the frontal cortex, and LCBF was measured by quantitative autoradiography by using 4-iodo[N-methyl-14C]antipyrine. Superfusion of an inhibitor of NO synthase, N omega-nitro-L-arginine (NA; 1 mM), for 45 min abolished the increase of LCBF induced by topical bicuculline methiodide (10 mM) [164 +/- 18 ml/100 g per min in the artificial cerebrospinal fluid (aCSF)-superfused side and 104 +/- 12 ml/100 g per ml in the NA-superfused side; P < 0.005]. This effect was reversed by coapplication of an excess of L-arginine substrate (10 mM) (218 +/- 22 ml/100 g per min in the aCSF-superfused side and 183 +/- 31 ml/100 g per min in the NA + L-Arg-superfused side) but not by 10 mM D-arginine, a stereoisomer with poor affinity for NO synthase (193 +/- 17 ml/100 g per min in the aCSF-superfused side and 139 +/- 21 ml/100 g per min in the NA + D-Arg-superfused side; P < 0.005). Superfusion of the guanylyl cyclase inhibitor methylene blue attenuated the LCBF increase elicited by topical bicuculline methiodide by 25% +/- 16% (P < 0.05). The present findings suggest that NO is the mediator of the vasodilation in response to focal epileptic seizures.
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PMID:Nitric oxide mediates the increase in local cerebral blood flow during focal seizures. 753 26

In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats. 753 78

In the present study, we examine the involvement of the L-arginine-nitric oxide pathway in seizure activity termination. Convulsions were induced reproducibly by intracerebroventricular administration of N-methyl-D-aspartate to conscious mice. The duration of the seizure activity was increased by inhibition of the NO-pathway or by intracerebroventricular injection of methylene blue, an inhibitor of guanylate cyclase activity. This increased duration in seizure activity was reversed by co-administration of L-arginine or by intracerebroventricular injection of guanosine 3':5' cyclic monophosphate (cGMP). These results suggest that nitric oxide produced in response to NMDA receptor activation leads to an increase in cGMP which induces the seizure activity termination.
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PMID:Nitric oxide: an endogenous anticonvulsant substance. 768 18

Microinjection of N-methyl-D-aspartate (NMDA; 1 and 2.5 nmol) or kainate (KA; 50 pmol) into the deep prepiriform cortex elicited behavioral signs of seizure activity. No epileptiform activity was observed after deep prepiriform cortex microinjection of either L-arginine (L-Arg, 5 and 10 nmol) or its D-enantiomer, D-arginine (D-Arg, 2.5-10 nmol). However, both the seizure score and the incidence of electroencephalographic (EEG) epileptic discharges elicited by NMDA (1 and 2.5 nmol) and KA (50 pmol) were significantly increased by L- but not D-Arg. The facilitatory effects of L-Arg on seizure activity elicited by both NMDA and KA were dose-dependent and could be prevented by co-administration of L-Arg (10 nmol) and the nitric oxide (NO) synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 20 nmol). Motor and electrocortical seizures were observed after microinjection of the NO donor sodium nitroprusside (SNP; 5 to 20 nmol) into the deep prepiriform cortex. Infusion of methylene blue (20 nmol), a soluble guanylate cyclase inhibitor, protected against SNP-induced seizures. Furthermore, prior infusion of a subconvulsant dose of SNP into the deep prepiriform cortex significantly potentiated the seizure activity elicited by either NMDA (1 and 2.5 nmol) or KA (50 pmol). These results support the proposal that NO is formed from L-Arg upon excitatory amino acid receptor activation within the deep prepiriform cortex, thereby contributing to the genesis of seizure activity.
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PMID:L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. 842 97

Carbon monoxide (CO) is an endogenously produced gas sharing many properties with nitric oxide (NO), notably activating soluble guanylate cyclase and relaxing blood vessels. The brain can generate high quantities of CO from a constitutive enzyme, haem oxygenase (HO-2). To determine whether CO is involved in the regulatory mechanisms of cerebral blood flow (CBF), two conditions associated with a reproducible CBF increase were studied in rats: epileptic seizures induced by kainate, and hypercapnia. The HO inhibitor tin protoporphyrin (Sn-PP) did not modify the basal level of CBF, significantly reduced the increase in CBF during status epilepticus, and did not affect the cerebrovascular response to hypercapnia. It is concluded that CO participates in the regulation of CBF in specific conditions, notably those associated with glutamate release.
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PMID:Carbon monoxide regulates cerebral blood flow in epileptic seizures but not in hypercapnia. 969 25


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