Inhibition of guanylate cyclase stimulation by NO and  bovine arterial relaxation to peroxynitrite and H2O2

The inhibitor of soluble guanylate cyclase (sGC) stimulation by nitric oxide (NO), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), was examined for its effects on the prolonged relaxation of endothelium-removed bovine coronary (BCA) and pulmonary (BPA) arteries to peroxynitrite (ONOO−) and on H2O2-elicited relaxation and sGC stimulation. Our previous studies suggest that ONOO− causes a prolonged relaxation of BPA by regenerating NO and that a 2-min exposure of BCA or BPA to 50 nM NO causes an ONOO−-elicited relaxation. The relaxation of K+-precontracted BCA to 50 nM NO or 100 μM ONOO− was essentially eliminated by 10 μM ODQ. ODQ also eliminated relaxation to 0.1 nM-10 μM of NO donor S-nitroso- N-acetyl-penicillamine (SNAP), but it did not alter relaxation to 1–300 μM H2O2. Similar responses were also observed in BPA. ODQ did not increase lucigenin-detectable superoxide production in BCA, and it did not alter luminol-detectable endogenous ONOO− formation observed during a 2-min exposure of BCA to 50 nM NO. In addition, ODQ did not affect tissue release of NO after 2 min exposure of BCA to 50 nM NO. The activity of sGC in BPA homogenate that is stimulated by endogenous H2O2was not altered by ODQ, whereas sGC activity in the presence of 10 μM SNAP (+fungal catalase) was reduced by ODQ. Thus relaxation of K+-precontracted BCA and BPA to ONOO− appears to be completely mediated by NO stimulation of sGC, whereas the actions of ODQ suggest that NO is not involved in H2O2-elicited relaxation and sGC stimulation. This study did not detect evidence for the participation of additional mechanisms potentially activated by ONOO− in the responses studied.

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NADPH and heme redox modulate pulmonary artery relaxation and guanylate cyclase activation by NO

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.6.l1124 ◽

1999 ◽

Vol 277 (6) ◽

pp. L1124-L1132 ◽

Cited By ~ 12

Author(s):

Sachin A. Gupte ◽

Tasneem Rupawalla ◽

Donald Phillibert ◽

Michael S. Wolin

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Pulmonary Arteries ◽

Redox Status ◽

Pentose Phosphate ◽

Inhibitory Effects ◽

No Donor ◽

Guanylate Cyclase Activation ◽

Stimulation Of

The hemoprotein oxidant ferricyanide (FeCN) converts the iron of the heme on soluble guanylate cyclase (sGC) from Fe2+ to Fe3+, which prevents nitric oxide (NO) from binding the heme and stimulating sGC activity. This study uses FeCN to examine whether modulation of the redox status of the heme on sGC influences the relaxation of endothelium-removed bovine pulmonary arteries (BPA) to NO. Pretreatment of the homogenate of BPA with 50 μM FeCN resulted in a loss of stimulation of sGC activity by the NO donor 10 μM S-nitroso- N-acetylpenicillamine (SNAP). In the FeCN-treated homogenate reconcentrated to the enzyme levels in BPA, 100 μM NADPH restored NO stimulation of sGC, and this effect of NADPH was prevented by an inhibitor of flavoprotein electron transport, 1 μM diphenyliodonium (DPI). In BPA the relaxation to SNAP was not altered by FeCN, inhibitors of NADPH generation by the pentose phosphate pathway [250 μM 6-aminonicotinamide (6-AN) and 100 μM epiandrosterone (Epi)], or 1 μM DPI. However, the combination of FeCN with 6-AN, Epi, or DPI inhibited ( P < 0.05) relaxation to SNAP without significantly altering the relaxation of BPA to forskolin. The inhibitory effects of 1 μM 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (a probe that appears to convert NO-heme of sGC to its Fe3+-heme form) on relaxation to SNAP were also enhanced by DPI. These observations suggest that a flavoprotein containing NADPH oxidoreductase may influence cGMP-mediated relaxation of BPA to NO by maintaining the heme of sGC in its Fe2+ oxidation state.

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Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models

Journal of Hypertension ◽

10.1097/hjh.0b013e32833b558c ◽

2010 ◽

Vol 28 (8) ◽

pp. 1666-1675 ◽

Cited By ~ 56

Author(s):

Yuliya Sharkovska ◽

Philipp Kalk ◽

Bettina Lawrenz ◽

Michael Godes ◽

Linda Sarah Hoffmann ◽

...

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Organ Damage ◽

Stimulation Of

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Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00224.2003 ◽

2004 ◽

Vol 286 (5) ◽

pp. L984-L991 ◽

Cited By ~ 57

Author(s):

Lisa K. Kelly ◽

Stephen Wedgwood ◽

Robin H. Steinhorn ◽

Stephen M. Black

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Primary Cultures ◽

No Donor ◽

Endothelin 1 ◽

Cgmp Analog ◽

Pulmonary Arterial ◽

Long Acting ◽

Arterial Endothelial Cells

The use of exogenous nitric oxide (NO) has been shown to alter the regulation of other endothelially derived mediators of vascular tone, such as endothelin-1 (ET-1). However, the interaction between NO and ET-1 appears to be complex and remains incompletely understood. One of the major actions of NO is the activation of soluble guanylate cyclase (sGC) with the subsequent generation of cGMP. Therefore, we undertook this study to test the hypothesis that NO regulates ET-1 production via the activation of the sGC/cGMP pathway. The results obtained indicated that the exposure of primary cultures of 4-wk-old ovine pulmonary arterial endothelial cells (4-wk PAECs) to the long-acting NO donor DETA NONOate induced both a dose- and time-dependent decrease in secreted ET-1. This decrease in ET-1 secretion occurred in the absence of changes in endothelin-converting enzyme-1 or sGC expression but in conjunction with a decrease in prepro-ET-1 mRNA. The changes in ET-1 release were inversely proportional to the cellular cGMP content. Furthermore, the NO-independent activator of sGC, YC-1, or treatment with a cGMP analog also produced significant decreases in ET-1 secretion. Conversely, pretreatment with the sGC inhibitor ODQ blocked the NO-induced decrease in ET-1. Therefore, we conclude that exposure of 4-wk PAECs to exogenous NO decreases secreted ET-1 resulting from the activation of sGC and increased cGMP generation.

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Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway

AJP Renal Physiology ◽

10.1152/ajprenal.1992.263.6.f1020 ◽

1992 ◽

Vol 263 (6) ◽

pp. F1020-F1025 ◽

Cited By ~ 9

Author(s):

R. M. Edwards ◽

M. Pullen ◽

P. Nambi

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Binding Sites ◽

Soluble Guanylate Cyclase ◽

Maximum Effect ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

High Affinity ◽

Dependent Pathway ◽

Stimulation Of

The effects of endothelins (ET) on guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact rat glomeruli were examined. ET-3 produced a rapid approximately fivefold increase in cGMP levels with the maximum effect occurring at 1 min. The ET-3-induced increase in cGMP accumulation occurred in the absence and presence of 3-isobutyl-1-methylxanthine. ET-1, ET-2, ET-3, and the structurally related toxin, sarafotoxin S6c, all increased glomerular cGMP levels in a concentration-dependent manner and with similar potencies (EC50 approximately 15-30 nM). The L-arginine analogue, N omega-nitro-L-arginine (L-NNA), reduced basal levels of cGMP and also totally inhibited ET-induced increases in cGMP as did methylene blue, an inhibitor of soluble guanylate cyclase. The effect of L-NNA was attenuated by L-arginine but not by D-arginine. The stimulation of cGMP accumulation by ET-3 was dependent on extracellular Ca2+ and was additive to atriopeptin III but not to acetylcholine. The ETA-selective antagonist, BQ 123, had no effect on ET-3-induced formation of cGMP. Glomerular membranes displayed high-affinity (Kd = 130-150 pM) and high-density (approximately 2.0 pmol/mg) binding sites for 125I-ET-1 and 125I-ET-3. ET-1, ET-3, and sarafotoxin S6c displaced 125I-ET-1 binding to glomerular membranes with similar affinities. BQ 123 had no effect on 125I-ET-1 binding. We conclude that ET increases cGMP levels in glomeruli by stimulating the formation of a nitric oxide-like factor that activates soluble guanylate cyclase. This effect of ET appears to be mediated by activation of ETB receptors and may serve to modulate the contractile effects of ET.

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Opposing actions of nitric oxide on synaptic inputs of identified interneurones in the central nervous system of the crayfish

Journal of Experimental Biology ◽

10.1242/jeb.204.7.1319 ◽

2001 ◽

Vol 204 (7) ◽

pp. 1319-1332 ◽

Cited By ~ 3

Author(s):

H. Aonuma ◽

P.L. Newland

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Sensory Nerve ◽

Signal Transduction Pathway ◽

Response Class ◽

No Donor ◽

Synaptic Inputs ◽

Class 1 ◽

Local Circuits

Little is known of the action of nitric oxide (NO) at the synaptic level on identified interneurones in local circuits that process mechanosensory signals. Here, we examine the action of NO in the terminal abdominal ganglion of the crayfish Pacifastacus leniusculus, where it has modulatory effects on the synaptic inputs of 17 identified ascending interneurones mediated by electrical stimulation of a sensory nerve. To analyse the role of NO in the processing of sensory signals, we bath-applied the NO donor SNAP, the NO scavenger PTIO, the nitric oxide synthase (NOS) inhibitor l-NAME, the NOS substrate l-arginine, a cyclic GMP (cGMP) analogue, 8-Br-cGMP, and the soluble guanylate cyclase (sGC) inhibitor ODQ. The effects of these chemicals on the synaptic inputs of the interneurones could be divided into two distinct classes. The NO donor SNAP enhanced the inputs to one class of interneurone (class 1) and depressed those to another (class 2). Neither the inactive isomer NAP nor degassed SNAP had any effect on the inputs to these same classes of interneurone. The NO scavenger PTIO caused the opposite effects to those of the NO donor SNAP, indicating that endogenous NO may have an action in local circuits. Preventing the synthesis of NO using l-NAME had the opposite effect to that of SNAP on each response class of interneurone. Increasing the synthesis of endogenous NO by applying l-arginine led to effects on both response classes of interneurone similar to those of SNAP. Taken together, these results suggested that NO was the active component in mediating the changes in amplitude of the excitatory postsynaptic potentials. Finally, the effects of 8-Br-cGMP were similar to those of the NO donor, indicating the possible involvement of a NO-sensitive guanylate cyclase. This was confirmed by preventing the synthesis of cGMP by sGC using ODQ, which caused the opposite effects to those of 8-Br-cGMP on the two response classes of interneurone. The results indicate that a NO-cGMP signal transduction pathway, in which NO regulates transmitter release from mechanosensory afferents onto intersegmental ascending interneurones, is probably present in the local circuits of the crayfish.

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Effects of nitroglycerin/L-cysteine on soluble guanylate cyclase: evidence for an activation/inactivation equilibrium controlled by nitric oxide binding and haem oxidation

Biochemical Journal ◽

10.1042/bj20050565 ◽

2005 ◽

Vol 390 (2) ◽

pp. 625-631 ◽

Cited By ~ 14

Author(s):

Antonius C. F. Gorren ◽

Michael Russwurm ◽

Alexander Kollau ◽

Doris Koesling ◽

Kurt Schmidt ◽

...

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Soret Band ◽

Flavin Mononucleotide ◽

Independent Manner ◽

No Donor ◽

No Release ◽

Glycerol Trinitrate ◽

Haem Protein

GTN (nitroglycerin; glycerol trinitrate) causes dilation of blood vessels via activation of nitric oxide (NO)-sensitive sGC (soluble guanylate cyclase), a heterodimeric haem protein that catalyses the conversion of GTP into cGMP. Activation of sGC by GTN requires enzymatic or non-enzymatic bioactivation of the nitrate. Based on insufficient NO release and lack of spectroscopic evidence for formation of NO–sGC, the cysteine (Cys)-dependent activation of sGC by GTN was proposed to occur in an NO-independent manner. This extraordinary claim is questioned by the present findings. First, the effect of GTN/Cys was blocked by the NO scavenger oxyhaemoglobin, the superoxide-generating compound flavin mononucleotide and the haem-site sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Secondly, at equi-effective concentrations, GTN/Cys and the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine released identical amounts of NO. Finally, at sufficiently high rates of NO release, activation of sGC by GTN/Cys was accompanied by a shift of the Soret band from 431 to 399 nm, indicating formation of NO–sGC. In the absence of Cys, GTN caused haem oxidation, apparent as a shift of the Soret band to 392 nm, which was accompanied by inactivation of the NO-stimulated enzyme. These results suggest that the effect of GTN/Cys is the result of an activation/inactivation equilibrium that is controlled by the rate of NO release and haem oxidation.

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The role of nitric oxide in the regulation of the electrical activity of the trigeminal nerve in the rat

10.34014/mpphe.2021-177-180 ◽

2021 ◽

Author(s):

S.O. Svitko ◽

K.S. Koroleva ◽

G.F. Sitdikova ◽

K.A. Petrova

Keyword(s):

Nitric Oxide ◽

Sodium Nitroprusside ◽

Trigeminal Nerve ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

No Synthase ◽

The Body ◽

No Donor ◽

No Signaling

Nitric oxide (NO) is a gaseous signaling molecule that regulates a number of physiological functions, including its role in the formation of migraine has been established. NO is endogenously produced in the body from L-arginine by NO synthase. The NO donor, nitroglycerin, is a trigger of migraine in humans and is widely used in the modeling of this disease in animals, which suggests the involvement of components of the NO signaling cascade in the pathogenesis of migraine. Based on the results obtained, it was found that an increase in the concentration of both the substrate for the synthesis of NO, L-arginine, and the NO donor, sodium nitroprusside, has a pro-nociceptive effect in the afferents of the trigeminal nerve. In this case, the effect of sodium nitroprusside is associated with the activation of intracellular soluble guanylate cyclase. Key words: nitric oxide, migraine, trigeminal nerve, L-arginine, guanylate cyclase, sodium nitroprusside, nociception.

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