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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional effects of G protein-linked glutamate receptor activation have been studied in mouse mesencephalic neurons in vitro. We have been able to identify two receptor classes, one linked to phosphoinositide hydrolysis and another that inhibits adenylate cyclase. The agonist (1S,3R)-aminocyclopentane-1,3-dicarboxylate (ACPD) affected the two responses with similar potency (EC50 = 2 and 7 microM, respectively). In contrast, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine selectively decreased adenylate cyclase activity (EC50 = 150 nM), without interfering with the phosphoinositide pathway. Activation of ion channel-linked glutamate receptors in mesencephalic neurons leads to cGMP formation. In this study, we demonstrate that cell pretreatment with ACPD or (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine prevented, in a dose-dependent fashion, N-methyl-D-aspartate (NMDA)-induced cGMP formation but not the kainate-stimulated response. The pharmacological profile suggests that receptors that are negatively coupled to adenylate cyclase are responsible for this effect. Coexposure of neurons to ACPD and Ba2+, a K+ channel blocker, counteracted the ACPD-induced blockade of NMDA receptors, suggesting that activation of K+ conductances could be involved in the post-transduction events triggered by metabotropic receptors in the mesencephalon. Neuronal treatment with NMDA for 10 min caused a reduction in mitochondrial activity. Direct inhibition of nitric oxide synthase with the inhibitor NG-nitro-L-arginine or removal of extracellular nitric oxide with reduced hemoglobin did not prevent this metabolic impairment, thus excluding a role for nitric oxide in this test for excitotoxicity. On the contrary, the mitochondrial function was maintained when neurons exposed to NMDA were preincubated with metabotropic receptor agonists. To summarize, our results suggest that metabotropic receptors that are negatively coupled to adenylate cyclase exert modulatory control specifically on NMDA receptor activity. This event could also contribute to the reduction of neurotoxic effects due to NMDA receptor hyperactivity.
Mol Pharmacol 1995 May
PMID:Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro. 774 73

It has been postulated that nitric oxide (NO) can react with superoxide anion (.O2-) to generate hydroxyl (.OH) radical. If this is correct, inhibition of NO synthesis could attenuate .OH radical mediated ischemia/reperfusion injury. Therefore we studied the effects of NG-nitro-L-arginine (L-NNA), a competitive inhibitor of the NO synthase enzyme on ischemia/reperfusion injury injury in isolated perfused rat hearts. Three groups of rats (n = 12-15) were studied. Group I: Untreated ischemia/reperfusion control (37.5 min of global ischemia followed by 20 min reperfusion); Group II: ischemia/reperfusion with 25 microM NG-nitro-L-arginine; and Group III: ischemia/reperfusion in the presence of L-NNA and 2 mM L-arginine, the substrate for NO synthase. Coronary flow (in ml/min) and ventricular developed pressure, +dP/dt and -dP/dt were measured 5 min prior to ischemia and at the end of reperfusion. Baseline preischemic developed pressure was significantly lower in L-NNA perfused hearts than controls (76.8 +/- 5.9 v 97.6 +/- 2.9 mmHg, P < 0.05). However, the developed pressure following reperfusion was significantly greater in L-NNA perfused hearts (57.4 +/- 7.4 v 20.8 +/- 6.4 mmHg in control). This protective effect was reversed by the addition of L-arginine. Preischemic coronary flow was decreased significantly in the L-NNA group (6.4 +/- 0.5 ml/min) compared to controls (11.6 +/- 0.7 ml/min). The duration of sinus rhythm was significantly improved from 3.8 +/- 1.2 min in controls to 15.1 +/- 0.8 min in L-NNA perfused hearts. A corresponding significantly lower incidence of arrhythmias was observed (10.2 +/- 1.5 in ischemia/reperfusion group v 1.7 +/- 0.8 min with L-NNA).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Jan
PMID:Sustained inhibition of nitric oxide by NG-nitro-L-arginine improves myocardial function following ischemia/reperfusion in isolated perfused rat heart. 776 Mar 62

In the present study oxidized low-density lipoproteins (ox-LDL) was prepared by a new simple method: oxidizing LDL by electrolysis-generated free radicals. In endothelium-intact norepinephrine(NE)-precontracted rabbit aortic rings, ox-LDL (2 mg protein/ml)-incubation for 30 min or 3 mM oleic acid for 10 min, significantly attenuated the acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR) (both P < 0.01 v control). Such attenuated EDR were sustained after washout. The oleic acid-induced endothelial dysfunction was associated with concomitant reduction of cGMP level in aortic rings. Preincubation of aortic rings with 500 microM L-arginine or 100 u/ml superoxide dismutase for 10 min partly prevented the oleic acid-induced attenuation of EDR and reduction of cGMP, indicating that oleic acid may impair the L-arginine-nitric acid pathway and/or inactivate the nitric oxide. Both ox-LDL and oleic acid potentiated NE-induced aortic ring contraction (both P < 0.01 v control). Such potentiating effects were abolished by preincubation with 1 microM verapamil, indicating the possible involvement of calcium influx in vascular smooth muscle cells during the enhanced contraction. Gas-chromatographic analysis showed that oleic acid content is the highest among all free fatty acids in ox-LDL. In conclusion, we found that oleic acid possesses certain similar vascular effects as ox-LDL in inducing endothelial dysfunction and in enhancing NE-induced vasocontraction in rabbit aortic ring. We proposed that the vasoactive effects of ox-LDL may be resulted partly from the activation or release of active oleic acid molecule during oxidative modification of LDL.
J Mol Cell Cardiol 1995 Jan
PMID:Some similarities in vascular effects of oleic acid and oxidized low-density lipoproteins on rabbit aorta. 776 Mar 74

Nitecapone [3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione], is a scavenger of nitric oxide produced in vitro. It reduced the rate of methemoglobin formation from oxyhemoglobin exposed to nitric oxide generated from the reaction of hydroxylamine with Complex I of catalase and it decreased the amount of nitrite formed in the reaction of oxygen with nitric oxide generated from sodium nitroprusside. Nitecapone also affected the L-arginine dependent accumulation of nitrite in a suspension of peritoneal rat neutrophils. The related compounds entacapone [2-cyano-N, N-diethyl-3-(3,4 dihydroxy-5-nitrobenzyl)-propenamide] and OR 1246 [3-(3,4-dihydroxy-5-nitrobenzyl)-2,4-pentanedione] were also able to scavenge nitric oxide. The action of nitecapone on nitric oxide expands the role of nitecapone as a scavenger of reactive oxygen species, and suggests nitecapone, entacapone and OR 1246 as potential therapeutic agents for the treatment of diseases connected with increased production of nitric oxide.
Biochem Mol Biol Int 1994 Oct
PMID:Nitecapone: a nitric oxide radical scavenger. 783 30

In 1991, we postulated that carbon monoxide, which is formed endogenously from heme catabolism catalyzed by heme oxygenase and shares some of the chemical and biological properties of nitric oxide, may play a role similar to that of nitric oxide as a widespread signal transduction mechanism for the regulation of cell function and communication. We review the experimental evidence that tests this postulate. Carbon monoxide appears to be involved in the neurophysiological phenomenon of long-term potentiation, which appears to play a key role in memory and learning. Zinc protoporphyrin, an inhibitor of heme oxygenase, prevents induction of long-term potentiation. Zinc protoporphyrin is an endogenous substance, the levels of which are increased in iron deficiency states and in lead poisoning, and by inhibiting heme oxygenase may modulate long-term potentiation and memory. It has been shown that, when cobalt protoporphyrin is injected into the medial nuclei of the rat hypothalamus, weight loss occurs. These nuclei contain heme oxygenase, and we postulate that weight loss is due to cobalt protoporphyrin induction of heme oxygenase and increased formation of carbon monoxide, which serves as a signal transduction mechanism in the medial hypothalamus to suppress appetite.
Cell Mol Biol (Noisy-le-grand) 1994 Nov
PMID:Heme oxygenase: the physiological role of one of its metabolites, carbon monoxide and interactions with zinc protoporphyrin, cobalt protoporphyrin and other metalloporphyrins. 784 53

We have studied the production of nitric oxide (NO) and superoxide by murine peritoneal macrophages during activation. The production of NO was induced by activation of cells with recombinant interferon-gamma (rIFN-gamma) and lipopolysaccharide (LPS). Phorbol 12-myristate 13-acetate (PMA)-induced formation of superoxide also increased during activation. However, NO released by the activated macrophages exerted the inhibitory effect on the superoxide formation in the same cells. This fact is supported by the increased production of superoxide when the cells were treated with NG-monomethyl-L-arginine (NGMMA) in addition to stimulation with rIFN-gamma and LPS. The production of superoxide was also inhibited by treatment with sodium nitroprusside (SPN), which spontaneously released nitric oxide in vitro, and at the same time there was increased adenosine diphosphate (ADP)-ribosylation of 37 kDa proteins of the cytoplasm. The 3-aminobenzamide (3-AB) treatment, which decreased ADP-ribosylation, partially reversed SNP-induced inhibition of superoxide generation in macrophages. The above data provide evidence that NO decreases superoxide formation possibly via ADP-ribosylation.
Biochem Mol Biol Int 1994 Aug
PMID:Generation of nitric oxide inhibits formation of superoxide in macrophages during activation. 784 11

Nitric oxide (NO) has been suggested to act as a regulator of endogenous intracellular ADP-ribosylation, based on radiolabelling of proteins in tissue homogenates incubated with [32P]NAD and NO. After the NO-stimulated modification was replicated in a defined system containing only the purified acceptor protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the hypothesis of NO-stimulation of an endogenous ADP-ribosyltransferase became moot. The NO-stimulated, NAD-dependent modification of GAPDH was recently characterized as covalent binding of the whole NAD molecule to the enzyme, not ADP-ribosylation. With this result, along with the knowledge that GAPDH is stoichiometrically S-nitrosylated, the role of NO in protein modification with NAD may be viewed as the conferring of an unexpected chemical reactivity upon GAPDH, possibly due to nitrosylation of a cysteine in the enzyme active site.
Mol Cell Biochem 1994 Sep
PMID:Nitric oxide and NAD-dependent protein modification. 789 64

We studied the localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase using in situ hybridization. The beta subunit was widely distributed in most neurons throughout the brain, with different levels of expression. The alpha 1 subunit was also distributed throughout the brain; however, it was located in more limited regions. Both subunits were expressed markedly in the glomerular layer of the olfactory bulb, dorsal and ventral striatum, and several regions in the brainstem. Regions with little or no alpha 1 subunit expression, but with marked expression of the beta 1 subunit included the olfactory bulb except for the glomerular layer, pyramidal cell layer in CA1 and granular cell layer in the dentate gyrus of the hippocampus, and many brainstem nuclei. The above regions expressing both subunits are suggested to contain active soluble guanylate cyclase as a target for nitric oxide, and thus may be involved in cellular signal transduction.
Brain Res Mol Brain Res 1993 Dec
PMID:Localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase in the rat brain. 790 52

Increased pain sensitivity (hyperalgesia) and persistent nociception following peripheral tissue injury depends both on an increase in the sensitivity of primary afferent nociceptors at the site of injury (peripheral sensitization), and on an increase in the excitability of neurons in the central nervous system (central sensitization). We will review evidence that central sensitization, and the persistent nociception it leads to, are dependent on an action of glutamate and aspartate at excitatory amino acid (EAA) receptors. Additional evidence will be presented implicating a role of various intracellular second messengers that are coupled to EAA receptors (nitric oxide, arachidonic acid, and protein kinase C) to central sensitization and persistent nociception following tissue injury. Finally, we will examine the evidence for a contribution of molecular events, including noxious stimulus-induced expression of immediate-early genes such as c-fos to persistent nociception.
Mol Neurobiol
PMID:The role of excitatory amino acid receptors and intracellular messengers in persistent nociception after tissue injury in rats. 791 27

The aim of these studies was to investigate the mechanism underlying the haemodynamic changes associated with brain death. The initial series of studies were to assess whether these changes involved some blood-borne factor. When control rats (n = 6) were exsanguinated whilst being simultaneously transfused with blood from rats that had been brain-dead for 60 min, their haemodynamic function did not deteriorate. Likewise, when brain-dead rats (n = 6) were exsanguinated and transfused with blood from control rats there was no improvement of haemodynamic function. The absence of any blood-borne factor was further confirmed in studies in which isolated hearts from control rats were perfused with blood from a support rat which had been brain-dead for 15 min (n = 6/group). The brain-death-induced haemodynamic changes in the support rat (mean arterial pressure increased from 98 +/- 6 to 176 +/- 9 mm Hg after 30 s and then fell to 44 +/- 5 mm Hg after 5 min) were not associated with changes in cardiac function of the perfused heart (left ventricular developed pressure was 146 +/- 4 mmHg before the induction of brain death and 147 +/- 4 and 151 +/- 7 mm Hg at 30 s and 5 min, respectively, after the induction). In further in vivo studies, we assessed the involvement of the autonomic nervous system in brain-death-induced haemodynamic instability. We achieved this by employing beta-adrenoreceptor blockade or bilateral vagotomy (n = 6/group); propranolol (1 mg/kg given as a bolus 6 min before brain death followed by 0.5 mg/kg/h continuous infusion) abolished the early transient tachycardia and positive inotropic response to brain death but did not alter the subsequent deterioration of function (mean arterial pressure fell from 75 +/- 7 mmHg before brain death to 49 +/- 5 mmHg after 30 min). Bilateral vagotomy had no effect on the functional changes induced by brain death. The effect of catecholamine depletion was then investigated; 6-hydroxydopamine (given over 15 days) depleted myocardial norepinephrine content by approximately 90% (from 2.3 +/- 0.1 to 0.3 +/- 0.1 nmol/g wet wt; P < 0.05). Depletion of cardiac catecholamines reduced brain-death-induced mortality to zero but did not affect cardiac dysfunction. Finally, we used L-NAME and naloxone in an attempt to identify roles for nitric oxide and endogenous opioid peptides but were again unable to influence the cardiac events. In conclusion, the initial transient hyperdynamic response induced by brain death appears to be mediated through cardiac innervation and can be inhibited by beta-adrenoreceptor blockade. However, the autonomic nervous system, nitric oxide, endogenous opioid peptides and blood-borne factors do not appear to be involved in the subsequent deterioration of cardiac function.
J Mol Cell Cardiol 1994 Apr
PMID:Brain-death-induced cardiac contractile dysfunction: studies of possible neurohormonal and blood-borne mediators. 791 33


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