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)

The discovery that nitric oxide (NO) has powerful vasoactive properties identical to those of endothelial-derived relaxing factor spawned a vast body of research investigating the physiological actions of small gas molecules. NO, which arises endogenously through the action of nitric oxide synthase (NOS) enzymes, is a highly reactive gas that plays important roles in the regulation of vascular and immune function. Carbon monoxide (CO), a similar yet much more chemically stable gas, occurs in nature as a product of the oxidation or combustion of organic materials. CO also arises in cells and tissues as a byproduct of heme oxygenase (HO) activity, which degrades heme to biliverdin-IXalpha. Like NO, CO acts as a vasorelaxant and may regulate other vascular functions such as platelet aggregation and smooth muscle proliferation. CO has also been implicated as a neurotransmitter in the central nervous system. HO-1, the inducible form of HO, confers cytoprotection against oxidative stress in vitro and in vivo. CO, when applied at low concentration, exerts potent cytoprotective effects mimicking those of HO-1 induction, including down-regulation of inflammation and suppression of apoptosis. Many of the effects of CO depend on the activation of guanylate cyclase, which generates guanosine 3',5'-monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) signaling pathways. This review highlights new advances in the interaction of CO with cellular signaling processes.
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PMID:Carbon monoxide: to boldly go where NO has gone before. 1511 2

Previous work has shown that nitric oxide (NO) mediates the antinociceptive effect of Crotalus durissus terrificus venom on carrageenin-induced hyperalgesia. In the present study the role of constitutive neuronal or of inducible form of nitric oxide synthase on venom effect was determined. The rat paw prostaglandin E(2) (PGE(2))-induced mechanical hyperalgesia model was used for nociceptive evaluation. The venom (200 microg/kg) administered per oz immediately before prostaglandin induced antinociception that persisted for 120 h. The characterisation of the antinociceptive effect of the venom in this model of hyperalgesia showed that kappa and delta-opioid receptors are involved in this effect. 7-nitroindazole (7-NI), a neuronal nitric oxide synthase (NOS) inhibitor, but not L-N(6)-(1-iminoethyl)lysine (L-NIL), an inhibitor of the inducible form of NOS, injected by intraplantar (i.pl.) route, antagonized the antinociceptive effect of the venom. The i.pl. administration of 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective guanylate cyclase inhibitor, blocked antinociception, whereas Rp-cGMP triethylamine, a cGMP-dependent protein kinase inhibitor, partially reversed this effect. These data indicate that peripheral kappa- and delta-opioid receptors are involved in the antinociceptive effect of Crotalus durissus terrificus on prostaglandin E(2)-induced hyperalgesia. Peripheral nitric oxide, generated by neuronal NO synthase, and cGMP/PKc are responsible, at least partially, for the molecular mechanisms of venom effect.
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PMID:Peripheral neuronal nitric oxide synthase activity mediates the antinociceptive effect of Crotalus durissus terrificus snake venom, a delta- and kappa-opioid receptor agonist. 1515 66

The scientific community has witnessed an exponential growth curve in the number of nitric oxide (NO) related publications over the last ten years. This diatomic radical is remarkably entangled (directly and indirectly) in a multitude of physiological and pathophysiological processes, including blood pressure regulation, inflammation, apoptosis, platelet adhesion, neurotransmission and host-defense mechanisms. Of the three known isozymes responsible for catalyzing the production of NO from L-arginine (L-Arg), it is the inducible form of nitric oxide synthase (iNOS) that we wish to examine here due to its involvement in a collection of diseases, including septic- and cytokine-induced shock, immune-type diabetes, rheumatoid arthritis, tissue damage, inflammation, and inflammatory bowel disease. Controlling the unregulated overproduction of NO from iNOS has been a formidable task; therapeutic intervention strategies range from preventing iNOS mRNA expression (anticytokine antibodies/receptor antagonists) to impeding NO action (NO scavengers, guanylyl cyclase inhibitors). Within these extremes lies the most conventional tactic, prohibiting NO production from iNOS with L-arginine competitive antagonists or irreversible enzyme inhibitors. This review will cover the more recent accounts gauged toward the identification and development of novel inhibitors of iNOS.
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PMID:Inhibition on inducible nitric oxide synthase. 1964 18

Endogenous carbon monoxide (CO) is generated through the heme oxygenase-catalysed degradation of heme and is now established as an important, biologically active molecule capable of modulating a number of signalling pathways. Such pathways include those involving nitric oxide/guanylate cyclase, reactive oxygen species (ROS) and MAP kinases. In the heart, up-regulation of the inducible form of heme oxygenase (HO-1) following stresses such as ischemia/reperfusion provides cardioprotection, and much evidence indicates that CO accounts for many of these beneficial effects. One target of CO appears to be the L-type Ca(2+) channel; CO inhibits recombinant and native forms of this cardiac channel via mitochondria-derived ROS, which likely contributes to the protective effects of CO. In stark contrast, exposure to exogenous CO is toxic: chronic, low-level exposure can lead to myocardial injury and fibrosis, whereas acute exposure is associated with life-threatening arrhythmias. The molecular mechanisms accounting for such effects remain to be elucidated, but require future study before the potentially beneficial effects of CO therapy can be safely exploited. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
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PMID:Carbon monoxide: a vital signalling molecule and potent toxin in the myocardium. 2164 Jul 28

Carbon monoxide (CO) is produced endogenously in the body as a byproduct of heme degradation catalyzed by the action of heme oxygenase (HO) enzymes. An inducible form, HO-1, responds to many factors such as oxidative stress, hypoxia, heme, bacterial endotoxins, proinflammatory cytokines and heavy metals. HO-2 is constitutively expressed under basal conditions in most human tissues including brain and gonads. Recent data show that CO is a gaseous mediator with multidirectional biological activity. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. CO shares many properties with another established vasodilatator and neurotransmitter - nitric oxide (NO). Both CO and NO are involved in neural transmission, modulation of blood vessel function and inhibition of platelet aggregation. The binding to guanylate cyclase, stimulation of the production of cGMP, activation of Ca2+-dependent potassium channels and stimulation of mitogen-activated protein kinases are well known cellular targets of CO action. Since CO is nowadays a subject of extensive investigation in many centers worldwide, the aim of the present study was to present the role of CO in various aspects of human physiology with special focus on its activity in the gastrointestinal tract.
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PMID:[Carbon monoxide in human physiology--its role in the gastrointestinal tract]. 2449 1


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