Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.
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PMID:NO-releasing hybrids of cardiovascular drugs. 1652 54

Sesamin, a major lignan in sesame seeds and oil, has been known to lower blood pressure in several types of experimental hypertensive animals. A recent study demonstrated that sesamin metabolites had in vitro radical-scavenging activities. Thus, we determined whether the antioxidative effect of sesamin metabolites modulate the vascular tone and contribute to the in vivo antihypertensive effect of sesamin. We used four demethylated sesamin metabolites: SC-1m (piperitol), SC-1 (demethylpiperitol), SC-2m [(1R,2S,5R,6S)-6-(4-hydroxy-3-methoxyphenyl)-2-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane], and SC-2 [(1R,2S,5R, 6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane]. SC-1, SC-2m, and SC-2, but not SC-1m, exhibited potent radical-scavenging activities against the xanthine/xanthine oxidase-induced superoxide production. On the other hand, SC-1m, SC-1, and SC-2m produced endothelium-dependent vasorelaxation in phenylephrine-precontracted rat aortic rings, whereas SC-2 had no effect. The SC-1m- and SC-1-induced vasorelaxations were markedly attenuated by pretreatment with a nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine (NOARG), or a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. Neither SC-1m nor SC-1 changed the expression level of endothelial NOS protein in aortic tissues. The antihypertensive effects of sesamin feeding were not observed in chronically NOARG-treated rats or in deoxycorticosterone acetate-salt-treated endothelial NOS-deficient mice. These findings suggest that the enhancement of endothelium-dependent vasorelaxation induced by sesamin metabolites is one of the important mechanisms of the in vivo antihypertensive effect of sesamin.
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PMID:Sesamin metabolites induce an endothelial nitric oxide-dependent vasorelaxation through their antioxidative property-independent mechanisms: possible involvement of the metabolites in the antihypertensive effect of sesamin. 1659 11

Myocardial infarction is a manifestation of necrotic cell death as a result of opening of the mitochondrial permeability transition (MPT). Receptor-mediated cardioprotection is triggered by an intracellular signaling pathway that includes phosphatidylinositol 3-kinase, endothelial nitric-oxide synthase, guanylyl cyclase, protein kinase G (PKG), and the mitochondrial K(ATP) channel (mitoK(ATP)). In this study, we explored the pathway that links mitoK(ATP) with the MPT. We confirmed previous findings that diazoxide and activators of PKG or protein kinase C (PKC) inhibited MPT opening. We extended these results and showed that other K(+) channel openers as well as the K(+) ionophore valinomycin also inhibited MPT opening and that this inhibition required reactive oxygen species. By using isoform-specific peptides, we found that the effects of K(ATP) channel openers, PKG, or valinomycin were mediated by a PKCepsilon. Activation of PKCepsilon by phorbol 12-myristate 13-acetate or H(2)O(2) resulted in mitoK(ATP)-independent inhibition of MPT opening, whereas activation of PKCepsilon by PKG or the specific PKCepsilon agonist psiepsilon receptor for activated C kinase caused mitoK(ATP)-dependent inhibition of MPT opening. Exogenous H(2)O(2) inhibited MPT, because of its activation of PKCepsilon, with an IC(50) of 0.4 (+/-0.1) microm. On the basis of these results, we propose that two different PKCepsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT.
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PMID:The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. 1672 May 72

In a preliminary experiment, we found that lavender essential oil relaxes vascular smooth muscle. Thus, the present experiments were designed to investigate the relaxation mechanism of linalyl acetate as the major ingredient of lavender essential oil in rabbit carotid artery specimens. Linalyl acetate produced sustained and progressive relaxation during the contraction caused by phenylephrine. The relaxation effect of linalyl acetate at a concentration near the EC50 was partially but significantly attenuated by nitroarginine as an inhibitor of nitric oxide synthase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one as an inhibitor of guanylyl cyclase, or by the denudation of endothelial cells. In specimens without endothelium, the phenylephrine-induced contraction and phosphorylation of myosin light chain (MLC) were significantly attenuated after the pretreatment with linalyl acetate. The relaxation caused by linalyl acetate in the endothelium-denuded specimens was clearly inhibited by calyculin A as an inhibitor of MLC phosphatase, although not by ML-9 as an inhibitor of MLC kinase. Furthermore, suppression of the phenylephrine-induced contraction and MLC phosphorylation with linalyl acetate was canceled by the pretreatment with calyculin A. These results suggest that linalyl acetate relaxes the vascular smooth muscle through partially activation of nitric oxide/cyclic guanosine monophosphate pathway, and partially MLC dephosphorylation via activating MLC phosphatase.
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PMID:Linalyl acetate as a major ingredient of lavender essential oil relaxes the rabbit vascular smooth muscle through dephosphorylation of myosin light chain. 1689 14

GABA is the inhibitory neurotransmitter in most brain stem nuclei. The properties of release of preloaded [(3)H]GABA were now investigated with slices from the mouse brain stem under normal and ischemic (oxygen and glucose deprivation) conditions, using a superfusion system. The ischemic GABA release increased about fourfold in comparison with normal conditions. The tyrosine kinase inhibitor genistein had no effect on GABA release, while the phospholipase inhibitor quinacrine reduced both the basal and K(+)-evoked release in normoxia and ischemia. The activator of protein kinase C (PKC) 4beta-phorbol 12-myristate 13-acetate had no effects on the releases, whereas the PKC inhibitor chelerythrine reduced the basal release in ischemia. When the cyclic guanosine monophosphate (cGMP) levels were increased by superfusion with zaprinast and other phosphodiesterase inhibitors, GABA release was reduced under normal conditions. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine (HA) enhanced the basal and K(+)-stimulated release by acting directly on presynaptic terminals. Under ischemic conditions GABA release was enhanced when cGMP levels were increased by zaprinast. This effect was confirmed by inhibition of the release by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The NO-producing agents SNAP, HA, and sodium nitroprusside potentiated GABA release in ischemia. These effects were reduced by the NO synthase inhibitor N(G)-nitro-L: -arginine, but not by ODQ. The results show that particularly NO and cGMP regulate both normal and ischemic GABA release in the brain stem. Their effects are however complex.
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PMID:Modulation of GABA release by second messenger substances and NO in mouse brain stem slices under normal and ischemic conditions. 1705 71

The dorsal lateral geniculate nucleus (dLGN) is essential for the transfer of visual information from the retina to visual cortex, and inhibitory mechanisms can play a critical in regulating such information transfer. Nitric oxide (NO) is an atypical neuromodulator that is released in gaseous form and can alter neural activity without direct synaptic connections. Nitric oxide synthase (NOS), an essential enzyme for NO production, is localized in thalamic inhibitory neurons and cholinergic brain stem neurons that innervate the thalamus, although NO-mediated effects on thalamic inhibitory activity remain unknown. We investigated NO effects on inhibitory activity in dLGN using an in vitro slice preparation. The NO donor, SNAP, selectively potentiated the frequency, but not amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in thalamocortical relay neurons. This increase also persisted in tetrodotoxin (TTX), consistent with an increase in GABA release from presynaptic terminals. The SNAP-mediated actions were attenuated not only by the NO scavenger carboxy-PTIO but also by the guanylyl cyclase inhibitor ODQ. The endogenous NO precursor L-arginine produced actions similar to those of SNAP on sIPSC activity and these L-arginine-mediated actions were attenuated by the NOS inhibitor L-NMMA acetate. The SNAP-mediated increase in sIPSC activity was observed in both dLGN and ventrobasal thalamic nucleus (VB) neurons. Considering the lack of interneurons in rodent VB, the NO-mediated actions likely involve an increase in the output of axon terminals of thalamic reticular nucleus neurons. Our results indicate that NO upregulates thalamic inhibitory activity and thus these actions likely influence sensory information transfer through thalamocortical circuits.
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PMID:Modulation of inhibitory activity by nitric oxide in the thalamus. 1737 43

The decrease of cyclic GMP (cGMP) level in the brain, contributing to cognitive and memory deficit in hyperammonemia (HA), has been attributed to the interference of ammonia with the NMDA/nitric oxide/soluble guanylate cyclase (GC)/cGMP pathway in neurons. The present study tested the hypotheses that (a) HA also affects cGMP synthesis elicited by stimulation of the natriuretic peptide receptor 2 (NPR-2) with its natural ligand, C-type natriuretic peptide (CNP) and (b) the latter effect may involve astrocytes, the ammonia-sensitive cells. In the cerebral cortical slices of control rats, CNP stimulated cGMP synthesis in a degree comparable to the NO donor, S-nitroso-N-acetylpenicillamine (SNAP) used at an optimal concentration. Fluoroacetate (FA), a metabolic inhibitor specifically affecting astrocytic mitochondria, inhibited the CNP-dependent cGMP synthesis by about 50%. Ammonium acetate-induced HA decreased by 68% the CNP-dependent cGMP generation in slices incubated in the absence of FA. In slices incubated in the presence of FA, cGMP synthesis in slices derived from HA rats did not differ from that in control slices. The results indicate that HA inhibits CNP-dependent cGMP synthesis in the FA-vulnerable, astrocytic compartment, but not in the FA-resistant compartment(s) of the brain. HA did not affect the expression of NPR-2 mRNA in the cerebral cortex tissue as tested using real-time PCR, indicating that the effect of ammonia involves as yet unidentified events occurring posttranscriptionally. Deregulation of NPR-2 function in astrocytes by ammonia may contribute to neurophysiological symptoms of HA.
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PMID:Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR-2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices. 1762 48

Nitric oxide (NO) is a physiologically important modulator of both vasomotor tone and platelet aggregability. These effects of NO are predominantly mediated by cyclic guanosine-3,'5'-monophosphate (cGMP) via activation of soluble guanylate cyclase. However, in patients with ischemic heart disease, platelets and coronary/peripheral arteries are hyporesponsive to the antiaggregatory and vasodilator effects of NO donors. NO resistance is also associated with a number of coronary risk factors and presents in different disease states. It correlates with conventional measures of "endothelial dysfunction," and represents a multifaceted disorder, in which smooth muscle and platelet NO resistance are equally important, as sites of abnormal NO-driven physiology. NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical (O(2)(-)) and of (reversible) inactivation of soluble guanylate cyclase. It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor, EDRF) and, as such, may contribute to the increased risk of ischemic events. Impairment in responsiveness to NO in ischemic patients implies a potential problem that those patients, in greatest need of nitrate therapy, may be least likely to respond. The prognostic impact of NO resistance at vascular and platelet levels has been demonstrated in patients with ischemic heart disease, and it has been shown that a number of agents (angiotensin-converting enzyme [ACE] inhibitors, perhexiline, insulin, and possibly statins) ameliorate this anomaly. The current review examines different aspects of the "NO resistance" phenomenon and discusses some related methodological issues.
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PMID:Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? 1776 75

The 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand of peroxisome proliferator-activated receptors gamma (PPAR-gamma) and is now recognized as a potent anti-inflammatory mediator. However, information regarding the influence of 15d-PGJ(2) on inflammatory pain is still unknown. In this study, we evaluated the effect of 15d-PGJ(2) upon inflammatory hypernociception and the mechanisms involved in this effect. We observed that intraplantar administration of 15d-PGJ(2) (30-300 ng/paw) inhibits the mechanical hypernociception induced by both carrageenan (100 mug/paw) and the directly acting hypernociceptive mediator, prostaglandin E(2) (PGE(2)). Moreover, 15d-PGJ(2) [100 ng/temporomandibular joint (TMJ)] inhibits formalin-induced TMJ hypernociception. On the other hand, the direct administration of 15d-PGJ(2) into the dorsal root ganglion was ineffective in blocking PGE(2)-induced hypernociception. In addition, the 15d-PGJ(2) antinociceptive effect was enhanced by the increase of macrophage population in paw tissue due to local injection of thioglycollate, suggesting the involvement of these cells on the 15d-PGJ(2)-antinociceptive effect. Moreover, the antinociceptive effect of 15d-PGJ(2) was also blocked by naloxone and by the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662), suggesting the involvement of peripheral opioids and PPAR-gamma receptor in the process. Similar to opioids, the 15d-PGJ(2) antinociceptive action depends on the nitric oxide/cGMP/protein kinase G (PKG)/K(ATP)(+) channel pathway because it was prevented by the pretreatment with the inhibitors of nitric-oxide synthase (N(G)-monomethyl-l-arginine acetate), guanylate cyclase]1H-(1,2,4)-oxadiazolo(4,2-alpha)quinoxalin-1-one[, PKG [indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycone (KT5823)], or with the ATP-sensitive potassium channel blocker glibenclamide. Taken together, these results demonstrate for the first time that 15d-PGJ(2) inhibits inflammatory hypernociception via PPAR-gamma activation. This effect seems to be dependent on endogenous opioids and local macrophages.
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PMID:15d-prostaglandin J2 inhibits inflammatory hypernociception: involvement of peripheral opioid receptor. 1792 70

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
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PMID:Prostacyclin among prostanoids. 1827 80


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