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)

Single injection of a small quantity of phenol into the cortex of one kidney in rats results in development of persistent hypertension (HTN) which is thought to be mediated by activation of renal afferent and efferent sympathetic pathways and sodium retention. Nitric oxide (NO) plays a major role in regulation of renal vascular resistance, tubular Na(+) reabsorption, pressure natriuresis, and thereby systemic arterial pressure. The present study was performed to test the hypothesis that chronic renal injury-induced HTN may be associated with dysregulation of NO system in the kidney. Accordingly, urinary NO metabolite (NO(x)) and cGMP excretions as well as renal cortical tissue (right kidney) expressions of NO synthase (NOS) isoforms [endothelial, neuronal, and inducible NOS, respectively (eNOS, nNOS, and iNOS)], NOS-regulatory factors (Caveolin-1, phospho-AKt, and calmodulin), and second-messenger system (soluble guanylate cyclase [sGC] and phosphodiesterase-5 [PDE-5]) were determined in male Sprague-Dawley rats 4 wk after injection of phenol (50 mul of 10% phenol) or saline into the lower pole of left kidney. The phenol-injected group exhibited a significant elevation of arterial pressure, marked reductions of urinary NO(x) and cGMP excretions, downregulations of renal tissue nNOS, eNOS, Phospho-eNOS, iNOS, and alpha chain of sGC. However, renal tissue AKt, phospho-AKT, Calmodulin, and PDE-5 proteins were unchanged in the phenol-injected animals. In conclusion, renal injury in this model results in significant downregulations of NOS isoforms and sGC and consequent reductions of NO production and cGMP generation by the kidney, events that may contribute to maintenance of HTN in this model.
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PMID:Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney. 1712 86

We characterized actions of hydrogen sulfide (H(2)S) on tension of isolated rat and mouse aortae, and then examined if H(2)S could directly modulate activity of endothelial nitric oxide (NO) synthase (eNOS). Isometric tension was recorded in rat and mouse aortic rings. Activity of recombinant bovine eNOS was determined as conversion of [(3)H]-arginine into [(3)H]-citrulline. NaHS, a H(2)S donor, caused contraction at low concentrations and relaxation at high concentrations in both rat and mouse aortae precontracted with phenylephrine. The contractile and relaxant effects of NaHS were enhanced and partially blocked, respectively, by the K(+)(ATP) channel inhibitor glibenclamide in the rat, but not mouse, aortae. In the KCl-precontracted rat aorta, NaHS produced glibenclamide-resistant contraction and relaxation. NaHS produced only relaxation, but not contraction, in the endothelium-denuded aortae, and also in the endothelium-intact aortae in the presence of inhibitors of NOS or soluble guanylate cyclase. NaHS pretreatment greatly attenuated the relaxation induced by acetylcholine, but not by an NO donor, in the tissues. Finally, we found that NaHS inhibited the conversion of [(3)H]-arginine into [(3)H]-citrulline by recombinant eNOS. NaHS thus causes contraction and relaxation in rat and mouse aortae. K(+)(ATP) channels are considered to contribute only partially to the NaHS-evoked relaxation. Most interestingly, our data demonstrate direct inhibition of eNOS by NaHS, probably responsible for its contractile activity, being evidence for a novel function of H(2)S.
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PMID:Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension. 1727 73

Nitric oxide (NO) plays a key role in regulating vascular tone. Mice overexpressing endothelial NO synthase [eNOS-transgenic (Tg)] have a 20% lower systemic vascular resistance (SVR) than wild-type (WT) mice. However, because eNOS enzyme activity is 10 times higher in tissue homogenates from eNOS-Tg mice, this in vivo effect is relatively small. We hypothesized that the effect of eNOS overexpression is attenuated by alterations in NO signaling and/or altered contribution of other vasoregulatory pathways. In isoflurane-anesthetized open-chest mice, eNOS inhibition produced a significantly greater increase in SVR in eNOS-Tg mice compared with WT mice, consistent with increased NO synthesis. Vasodilation to sodium nitroprusside (SNP) was reduced, whereas the vasodilator responses to phosphodiesterase-5 blockade and 8-bromo-cGMP (8-Br-cGMP) were maintained in eNOS-Tg compared with WT mice, indicating blunted responsiveness of guanylyl cyclase to NO, which was supported by reduced guanylyl cyclase activity. There was no evidence of eNOS uncoupling, because scavenging of reactive oxygen species (ROS) produced even less vasodilation in eNOS-Tg mice, whereas after eNOS inhibition the vasodilator response to ROS scavenging was similar in WT and eNOS-Tg mice. Interestingly, inhibition of other modulators of vascular tone [including cyclooxygenase, cytochrome P-450 2C9, endothelin, adenosine, and Ca-activated K(+) channels] did not significantly affect SVR in either eNOS-Tg or WT mice, whereas the marked vasoconstrictor responses to ATP-sensitive K(+) and voltage-dependent K(+) channel blockade were similar in WT and eNOS-Tg mice. In conclusion, the vasodilator effects of eNOS overexpression are attenuated by a blunted NO responsiveness, likely at the level of guanylyl cyclase, without evidence of eNOS uncoupling or adaptations in other vasoregulatory pathways.
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PMID:Vasomotor control in mice overexpressing human endothelial nitric oxide synthase. 1749 13

The endothelium lines the luminal surface of every blood vessel, allowing it contact with circulating blood elements, as well as the underlying vascular smooth muscle layer. In healthy vessels, the endothelium expresses constitutive forms of nitric oxide synthase (NOSIII) and cyclo-oxygenase (COX-1), which produce the vasoactive hormones NO and prostacyclin, respectively. Both NO and prostacyclin relax blood vessels and inhibit platelet activation. The actions of prostacyclin are mediated by cell surface prostacyclin (IP) receptors and/or intracellular peroxisome proliferator-activated receptors (PPAR) beta. The actions of NO are mediated predominately by activation of intracellular guanylyl cyclase, leading to the formation of cGMP. In platelets, the actions of NO and prostacyclin are synergistic, but in vessels their actions are additive. In diseased vessels, inducible forms of NOS (NOSII) and cyclo-oxygeanse (COX-2) are expressed in vascular smooth muscle, resulting in the release of large amounts of NO, prostacyclin and prostaglandin E2. The relative contribution of NOSII and COX-2 to vascular inflammation is still debated, but is likely to result in both protective and damaging responses. The relative contribution of constitutive forms of NOS and COX, as well as interactions between IP, PPAR beta and guanylyl cyclase pathways in vessels and platelets, is discussed.
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PMID:Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. 1796 42

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

Endothelial dysfunction in the setting of cardiovascular risk factors such as hypercholesterolemia, diabetes mellitus, chronic smoking, as well hypertension, is, at least in part, dependent of the production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). ROS-producing enzymes involved in increased oxidative stress within vascular tissue include NADPH oxidase, xanthine oxidase, and mitochondrial superoxide producing enzymes. Superoxide produced by the NADPH oxidase may react with NO, thereby stimulating the production of the NO/superoxide reaction product peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, therefore switching an antiatherosclerotic NO producing enzyme to an enzyme that may accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and also occurs within the smooth muscle cell layer. Increased superoxide production has important consequences with respect to signaling by the soluble guanylate cyclase and the cGMP-dependent kinase I, which activity and expression is regulated in a redox-sensitive fashion. The present review will summarize current concepts concerning eNOS uncoupling, with special focus on the role of tetrahydrobiopterin in mediating eNOS uncoupling.
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PMID:Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. 1832 Dec 9

The aim of this work was to investigate in the avascular heart of the frog Rana esculenta the influence of nitric oxide (NO) on ventricular systolic and diastolic functions by using a novel image analysis technique. The external volume variations of the whole ventricle were monitored during the heart cycle by video acquisition(visible light) and analysed by an appropriately developed software with a specific formula for irregular convex solids. The system, which measures the rate of volume changes and the ejection fraction, directly determined the volumetric behaviour of the working frog heart after stimulation or inhibition of NOS-NOcGMP pathway. End-diastolic volume (EDVext), end-systolic volume (ESVext), contraction and relaxation velocities (dV/dtsys and dV/dtdia, respectively), stroke volume (SV) and ejection fraction (EF), were measured before and after perfusion with NOS substrate (L-arginine), NO donor (SIN-1), cGMP analogue (8-Br-cGMP),NOS inhibitors (NG-monomethyl-L-arginine, L-NMMA; L-N(5)-(1-iminoethyl)-ornithine, L-NIO; 7-Nitroindazole,7-NI) and guanylyl cyclase inhibitor (ODQ). The results showed that NO reduces ventricular systolicfunction improving diastolic filling, while NOS inhibition increases contractility impairing ventricular filling capacity. The presence of activated eNOS (p-eNOS) was morphologically documented, further supporting that the mechanical activity of the ventricular pump in frog is influenced by a tonic release of NOS-generated NO.
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PMID:Nitric oxide modulates the frog heart ventricle morphodynamics. 1858 70

Microglia migrate rapidly to lesions in the central nervous system (CNS), presumably in response to chemoattractants including ATP released directly or indirectly by the injury. Previous work on the leech has shown that nitric oxide (NO), generated at the lesion, is both a stop signal for microglia at the lesion and crucial for their directed migration from hundreds of micrometers away within the nerve cord, perhaps mediated by a soluble guanylate cyclase (sGC). In this study, application of 100 microM ATP caused maximal movement of microglia in leech nerve cords. The nucleotides ADP, UTP, and the nonhydrolyzable ATP analog AMP-PNP (adenyl-5'-yl imidodiphosphate) also caused movement, whereas AMP, cAMP, and adenosine were without effect. Both movement in ATP and migration after injury were slowed by 50 microM reactive blue 2 (RB2), an antagonist of purinergic receptors, without influencing the direction of movement. This contrasted with the effect of the NO scavenger cPTIO (2-(4-carboxyphenyl)-4,4,5,5-teramethylimidazoline-oxyl-3-oxide), which misdirected movement when applied at 1 mM. The cPTIO reduced cGMP immunoreactivity without changing the immunoreactivity of eNOS (endothelial nitric oxide synthase), which accompanies increased NOS activity after nerve cord injury, consistent with involvement of sGC. Moreover, the sGC-specific inhibitor LY83583 applied at 50 microM had a similar effect, in agreement with previous results with methylene blue. Taken together, the experiments support the hypothesis that ATP released directly or indirectly by injury activates microglia to move, whereas NO that activates sGC directs migration of microglia to CNS lesions.
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PMID:ATP and NO dually control migration of microglia to nerve lesions. 1902 30

Nitric oxide (NO) produced in the heart by nitric oxide synthase (NOS) is a highly reactive signaling molecule and an important modulator of myocardial function. NOS catalyzes the conversion of L: -arginine to L: -citrulline and NO but under particular circumstances reactive oxygen species (ROS) can be formed instead of NO (uncoupling). In the heart, three NOS isoforms are present: neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3) are constitutively present enzymes in distinct subcellular locations within cardiomyocytes, whereas inducible NOS (iNOS, NOS2) is absent in the healthy heart, but its expression is induced by pro-inflammatory mediators. In the tissue, NO has two main effects: (i) NO stimulates the activity of guanylate cyclase, leading to cGMP generation and activation of protein kinase G, and (ii) NO nitrosylates tyrosine and thiol-groups of cysteine in proteins. Upon nitrosylation, proteins may change their properties. Changes in (i) NOS expression and activity, (ii) subcellular compartmentation of NOS activity, and (iii) the occurrence of uncoupling may lead to multiple NO-induced effects, some of which being particularly evident during myocardial overload as occurs during aortic constriction and myocardial infarction. Many of these NO-induced effects are considered to be cardioprotective but particularly if NOS becomes uncoupled, formation of ROS in combination with a low NO bioavailability predisposes for cardiac damage.
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PMID:Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. 1961 22

The aim of this research is to investigate the vasorelaxing effects and mechanisms involved in the phytoestrogen alpha-zearalanol (alpha-ZAL) in rat thoracic aortas rings. Intact or endothelium denuded rat thoracic aortas rings were put in individual organ chamber to observe the endothelium-dependent or independent vasorelaxing effects of alpha-ZAL (10(-10)-10(-5) M). The thoracic aortas rings were pre-contracted with phenylephrine. The relaxing effects of alpha-ZAL were observed and the influence of N(omega)-nitro-L-arginine methylester (L-NAME, NOS inhibitor), methylene blue (MB, guanylate cyclase inhibitor), charybdotoxin (ChTX, Ca(2+)-activated K+ channel blocker), glibenclamide (ATP-sensitive K+ channel blocker), (-) BayK8644 (L-type Ca2+ channel agonist) and ICI182,780 (estrogen receptor antagonist) were pre-incubated with alpha-ZAL, respectively, to explore the possible mechanisms involved in this vasorelaxation. Furthermore, the Phospho-eNOS expression and cGMP level in the aortas tissue were detected by Western blot and radioimmunity, respectively; the NO level in perfusate was assaied by chromatometry. Our result showed that alpha-ZAL (10(-10)-10(-5) M) induced both endothelium-dependent and -independent relaxation of rat thoracic aortas rings. The vasorelaxing effects of alpha-ZAL were dose-dependent whether the endothelium was intact or not. In endothelium-intact aortas rings, alpha-ZAL-induced vasorelaxation might be inhibited by L-NAME, MB, charybdotoxin, glibenclamide and (-) BayK8644, but not ICI182,780. (-) BayK8644 could also inhibit alpha-ZAL-induced vasorelaxation in endothelium-denuded aortas rings.10(-7)-10(-5) M alpha-ZAL might induce the Phospho-eNOS expression in thoracic aorta tissue, increase the NO level in perfusate and cGMP content in thoracic aorta tissue. Meanwhile, L-NAME might decrease both NO and its downstream cGMP level. Methylene blue might decrease the level of cGMP. These results suggest that alpha-ZAL induces a partly endothelium-dependent relaxation of rat thoracic aortas rings; the possible mechanisms involved in this rapid vasorelaxation include activation of eNOS/NO/cGMP pathway, opening of VSMCs ATP-sensitive and Ca(2+)-activated K+ channels through secretion of EDHF from endothelium. Furthermore, this relaxation also appears to be mediated by both direct and indirect inhibition of voltage-dependent Ca2+ channel of VSMCs, while it is not concerned with activation of estrogen receptor.
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PMID:Relaxing effects of phytoestrogen alpha-zearalanol on rat thoracic aorta rings in vitro. 1976 45


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