Journal articles: 'NO-cGMP pathway'

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Denninger, John W., and Michael A. Marletta. "Guanylate cyclase and the ⋅NO/cGMP signaling pathway." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1411, no. 2-3 (May 1999): 334–50. http://dx.doi.org/10.1016/s0005-2728(99)00024-9.

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YU, DOU, and WILLIAM D. ELDRED. "Gycine and GABA interact to regulate the nitric oxide/cGMP signaling pathway in the turtle retina." Visual Neuroscience 22, no. 6 (November 2005): 825–38. http://dx.doi.org/10.1017/s0952523805226123.

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Nitric oxide (NO) is a free radical that is important in retinal signal transduction and cyclic guanosine monophosphate (cGMP) is a critical downstream messenger of NO. The NO/cGMP signaling pathway has been shown to modulate neurotransmitter release and gap junction coupling in horizontal cells and amacrine cells, and increase the gain of the light response in photoreceptors. However, many of the mechanisms controlling the production of NO and cGMP remain unclear. Previous studies have shown activation of NO/cGMP production in response to stimulation with N-methyl-d-aspartate (NMDA) or nicotine, and the differential modulation of cGMP production by GABAA and GABAC receptors (GABAARs and GABACRs). This study used cGMP immunocytochemistry and NO imaging to investigate how the inhibitory GABAergic and glycinergic systems modulate the production of NO and cGMP. Our data show that blocking glycine receptors (GLYR) with strychnine (STRY) produced moderate increases in cGMP-like immunoreactivity (cGMP-LI) in select types of amacrine and bipolar cells, and strong increases in NO-induced fluorescence (NO-IF). TPMPA, a selective GABACR antagonist, greatly reduced the increases in cGMP-LI stimulated by STRY, but did not influence the increase in NO-IF stimulated by STRY. Bicuculline (BIC), a GABAAR antagonist, however, enhanced the increases in both the cGMP-LI and NO-IF stimulated by STRY. CNQX, a selective antagonist for α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid hydrobromide/kainic acid (AMPA/KA) receptors, eliminated both the increases in cGMP-LI and NO-IF stimulated by STRY, while MK801, a selective antagonist for NMDA receptors, slightly increased the cGMP-LI and slightly decreased the NO-IF stimulated by STRY. Finally, double labeling of NO-stimulated cGMP and either GLY or GABA indicated that cGMP predominantly colocalized with GLY. Taken together, these findings support the hypothesis that GLY and GABA interact in the regulation of the NO/cGMP signaling pathway, where GLY primarily inhibits NO production and GABA has a greater effect on cGMP production. Such interacting inhibitory pathways could shape the course of signal transduction of the NO/cGMP pathway under different physiological situations.

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Frank, Deborah U., Damian J. Horstman, Geoffrey N. Morris, Roger A. Johns, and George F. Rich. "Regulation of the endogenous NO pathway by prolonged inhaled NO in rats." Journal of Applied Physiology 85, no. 3 (September 1, 1998): 1070–78. http://dx.doi.org/10.1152/jappl.1998.85.3.1070.

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Nitric oxide (NO) modulates the endogenous NO-cGMP pathway. We determined whether prolonged inhaled NO downregulates the NO-cGMP pathway, which may explain clinically observed rebound pulmonary hypertension. Rats were placed in a normoxic (N; 21% O2) or hypoxic (H; 10% O2) environment with and without inhaled NO (20 parts/million) for 1 or 3 wk. Subsequently, nitric oxide synthase (NOS) and soluble guanylate cyclase (GC) activity and endothelial NOS (eNOS) protein levels were measured. Perfusate cGMP levels and endothelium-dependent and -independent vasodilation were determined in isolated lungs. eNOS protein levels and NOS activity were not altered by inhaled NO in N or H rats. GC activity was decreased by 60 ± 10 and 55 ± 11% in N and H rats, respectively, after 1 wk of inhaled NO but was not affected after 3 wk. Inhaled NO had no effect on perfusate cGMP in N lungs. Inhaled NO attenuated the increase in cGMP levels caused by 3 wk of H by 57 ± 11%, but there was no rebound in cGMP after 24 h of recovery. Endothelium-dependent vasodilation was not altered, and endothelium-independent vasodilation was not altered (N) or slightly increased (H, 10 ± 3%) by prolonged inhaled NO. In conclusion, inhaled NO did not alter the endogenous NO-cGMP pathway as determined by eNOS protein levels, NOS activity, or endothelium-dependent vasodilation under N and H conditions. GC activity was decreased after 1 wk; however, GC activity was not altered by 3 wk of inhaled NO and endothelium-independent vasodilation was not decreased.

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YU, DOU, and WILLIAM D. ELDRED. "GABAAand GABACreceptor antagonists increase retinal cyclic GMP levels through nitric oxide synthase." Visual Neuroscience 20, no. 6 (November 2003): 627–37. http://dx.doi.org/10.1017/s0952523803206052.

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The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signal transduction pathway plays a role in every retinal cell type. Previous studies have shown that excitatory glutamatergic synaptic pathways can increase cGMP-like immunoreactivity (cGMP-LI) in retina through stimulation of NO production, but little is known about the role of synaptic inhibition in the modulation of cGMP-LI. Gamma-amino-n-butyric acid (GABA) plays critical roles in modulating excitatory synaptic pathways in the retina. Therefore, we used GABA receptor antagonists to explore the role of GABAergic inhibitory synaptic pathways on the modulation of the NO/cGMP signal-transduction system. Cyclic GMP immunocytochemistry was used to investigate the effects of the GABA receptor antagonists bicuculline, picrotoxin, and (1,2,5,6-tetrahyropyridin-4-yl) methylphosphinic acid (TPMPA) on levels of cGMP-LI. Cyclic GMP-LI was strongly increased in response to the GABAAreceptor antagonist bicuculline, while the GABACreceptor antagonist TPMPA had little effect on cGMP-LI. The GABAA/GABACreceptor antagonist, picrotoxin, caused a moderate increase in cGMP-LI, which was mimicked by the combination of bicuculline and TPMPA. The nitric oxide synthase inhibitor, S-methyl-L-thiocitrulline (SMTC), blocked the increased cGMP-LI in response to stimulation with either bicuculline or picrotoxin. Treatments with either of the glutamate receptor antagonists (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) partially blocked the increases in cGMP-LI seen in response to bicuculline, but a combination of MK-801 and CNQX completely eliminated these increases. These results suggest that inhibitory synaptic pathways involving both types of GABA receptors work through excitatory glutamatergic receptors to regulate the NO/cGMP signal-transduction pathway in retina.

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Pérez-Sala, Dolores, Eva Cernuda-Morollón, Manuela Díaz-Cazorla, Fernando Rodríguez-Pascual, and Santiago Lamas. "Posttranscriptional regulation of human iNOS by the NO/cGMP pathway." American Journal of Physiology-Renal Physiology 280, no. 3 (March 1, 2001): F466—F473. http://dx.doi.org/10.1152/ajprenal.2001.280.3.f466.

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Nitric oxide (NO) and cGMP may exert positive or negative effects on inducible NO synthase (iNOS) expression. We have explored the influence of the NO/cGMP pathway on iNOS levels in human mesangial cells. Inhibition of NOS activity during an 8-h stimulation with IL-1β plus tumor necrosis factor (TNF)-α reduced iNOS levels, while NO donors amplified iNOS induction threefold. However, time-course studies revealed a subsequent inhibitory effect of NO donors on iNOS protein and mRNA levels. This suggests that NO may contribute both to iNOS induction and downregulation. Soluble guanylyl cyclase (sGC) activation may be involved in these effects. Inhibition of sGC attenuated IL-1β/TNF-α-elicited iNOS induction and reduced NO-driven amplification. Interestingly, cGMP analogs also modulated iNOS protein and mRNA levels in a biphasic manner. Inhibition of transcription unveiled a negative posttranscriptional modulation of the iNOS transcript by NO and cGMP at late times of induction. Supplementation with 8-bromo-cGMP (8-BrcGMP) reduced iNOS mRNA stability by 50%. These observations evidence a complex feedback regulation of iNOS expression, in which posttranscriptional mechanisms may play an important role.

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Hamid, S. A., M. Totzeck, C. Drexhage, I. Thompson, R. C. Fowkes, T. Rassaf, and G. F. Baxter. "NO/cGMP pathway in adrenomedullin mediated cardioprotection in mouse." Journal of Molecular and Cellular Cardiology 42, no. 6 (June 2007): S195. http://dx.doi.org/10.1016/j.yjmcc.2007.03.592.

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Morris, R., E. Southam, S. R. Gittins, J. Vente, and J. Garthwaite. "The NO-cGMP Pathway in Neonatal Rat Dorsal Horn." European Journal of Neuroscience 6, no. 5 (May 1994): 876–79. http://dx.doi.org/10.1111/j.1460-9568.1994.tb00998.x.

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Stojanovic, Aleksandra, Jasna A. Marjanovic, Viktor Brokovych, Randal A. Skidgel, Nissim Hay, and Xiaoping Du. "AKT Mediates Platelet Activation by Stimulating Nitric Oxide Synthesis and cGMP Elevation." Blood 106, no. 11 (November 16, 2005): 1652. http://dx.doi.org/10.1182/blood.v106.11.1652.1652.

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Abstract Phosphoinositide 3-kinase (PI3-K) and Akt play important roles in platelet activation. However, the downstream mechanisms for their roles are unclear. We have recently shown that nitric oxide (NO) synthase 3 (NOS3) and cGMP-dependent protein kinase stimulate platelet secretion and aggregation. Here we show that PI3-K-mediated Akt activation plays a critical role in agonist-stimulated platelet NO synthesis and cGMP elevation. Agonist-induced elevation of NO and cGMP was inhibited by Akt inhibitors and reduced in Akt-1 knockout platelets. Akt-1 knockout or Akt inhibitor-treated platelets showed reduced platelet secretion and aggregation in response to low concentrations of agonists, which can be reversed by low concentrations of sodium nitroprusside (SNP) or cGMP analogs. Similarly, PI3-K inhibitors diminished elevation of cGMP and also inhibited platelet secretion and the second-wave platelet aggregation, which was also partially reversed by cGMP analogs and by SNP. These results indicate that the NO-cGMP pathway is an important downstream mechanism mediating PI3-K and Akt signals leading to platelet secretion and aggregation. Conversely, the PI3-K-Akt pathway is a major upstream mechanism responsible for activating the NO-cGMP pathway. Thus, this study delineates a novel platelet activation pathway involving sequential activation of PI3-K, Akt, NOS3, sGC, and cGMP-dependent protein kinase.

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Paolillo, Michael, Stefanie Peters, Andrea Schramm, Jens Schlossmann, and Robert Feil. "Real-Time Imaging Reveals Augmentation of Glutamate-Induced Ca2+ Transients by the NO-cGMP Pathway in Cerebellar Granule Neurons." International Journal of Molecular Sciences 19, no. 8 (July 26, 2018): 2185. http://dx.doi.org/10.3390/ijms19082185.

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Dysfunctions of NO-cGMP signaling have been implicated in various neurological disorders. We have studied the potential crosstalk of cGMP and Ca2+ signaling in cerebellar granule neurons (CGNs) by simultaneous real-time imaging of these second messengers in living cells. The NO donor DEA/NO evoked cGMP signals in the granule cell layer of acute cerebellar slices from transgenic mice expressing a cGMP sensor protein. cGMP and Ca2+ dynamics were visualized in individual CGNs in primary cultures prepared from 7-day-old cGMP sensor mice. DEA/NO increased the intracellular cGMP concentration and augmented glutamate-induced Ca2+ transients. These effects of DEA/NO were absent in CGNs isolated from knockout mice lacking NO-sensitive guanylyl cyclase. Furthermore, application of the cGMP analogues 8-Br-cGMP and 8-pCPT-cGMP, which activate cGMP effector proteins such as cyclic nucleotide-gated cation channels and cGMP-dependent protein kinases (cGKs), also potentiated glutamate-induced Ca2+ transients. Western blot analysis failed to detect cGK type I or II in our primary CGNs. The addition of phosphodiesterase (PDE) inhibitors during cGMP imaging showed that CGNs degrade cGMP mainly via Zaprinast-sensitive PDEs, most likely PDE5 and/or PDE10, but not via PDE1, 2, or 3. In sum, these data delineate a cGK-independent NO-cGMP signaling cascade that increases glutamate-induced Ca2+ signaling in CGNs. This cGMP–Ca2+ crosstalk likely affects neurotransmitter-stimulated functions of CGNs.

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Su, Jun, Shengjun Zhang, James Tse, Peter M. Scholz, and Harvey R. Weiss. "Alterations in nitric oxide-cGMP pathway in ventricular myocytes from obese leptin-deficient mice." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 5 (November 2003): H2111—H2117. http://dx.doi.org/10.1152/ajpheart.00316.2003.

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Leptin is a regulator of body weight and affects nitric oxide (NO) production. This study was designed to determine whether the myocardial NO-cGMP signal transduction system was altered in leptin-deficient obese mice. Contractile function, guanylyl cyclase activity, and cGMP-dependent protein phosphorylation were assessed in ventricular myocytes isolated from genetically obese (B6.V-Lepob) and age-matched lean (C57BL/6J) mice. There were no differences in baseline contraction between the lean and obese groups. After stimulation with the NO donor S-nitroso- N-acetyl-penicillamine (SNAP, 10–6and 10–5M) or a membrane-permeable cGMP analog 8-bromo-cGMP (8-Br-cGMP, 10–6and 10–5M), cell contractility was depressed. However, 8-Br-cGMP had significantly greater effects in obese mice than in lean controls with percent shortening reduced by 47 vs. 39% and maximal rate of shortening decreased by 46 vs. 36%. The negative effects of SNAP were similar between the two groups. Soluble guanylyl cyclase activity was not attenuated. This suggests that the activity of the cGMP-independent NO pathway may be enhanced in obesity. The phosphorylated protein profile of cGMP-dependent protein kinase showed that four proteins were more intensively phosphorylated in obese mice, which suggests an explanation for the enhanced effect of cGMP. These results indicate that the NO-cGMP signaling pathway was significantly altered in ventricular myocytes from the leptin-deficient obese mouse model.

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Steiner, Alexandre A., Jose Antunes-Rodrigues, Samuel M. McCann, and Luiz G. S. Branco. "Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic region of the rat brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 282, no. 2 (February 1, 2002): R584—R593. http://dx.doi.org/10.1152/ajpregu.00391.2001.

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We tested the hypothesis that nitric oxide (NO) acts in the anteroventral preoptic region (AVPO) modulating fever. To this end, body core temperature (Tc) of rats was monitored by biotelemetry before and after pharmacological modulation of the NO pathway. Nitrite/nitrate and cGMP in the anteroventral third ventricular region (AV3V), where the AVPO is located, were also determined. Intra-AVPO microinjection of the NO synthase (NOS) inhibitor N G-monomethyl-l-arginine (l-NMMA, 12.5 μg) did not affect basal Tc, but it enhanced the early stage of lipopolysaccharide (LPS) fever, indicating that NO plays an antipyretic role in the AVPO. In agreement, intra-AVPO microinjection of the NO donor sodium nitroprusside (5 μg) reduced Tc. The antipyretic effect of NO seems to be mediated by cGMP because 1) NO has been shown to activate soluble guanylate cyclase, 2) intra-AVPO microinjection of 8-bromo-cGMP (8-BrcGMP) reduced Tc, and 3) the changes in AV3V levels of nitrite/nitrate and cGMP were similar in the course of fever. Additionally, we observed that nitrite/nitrate and cGMP levels decreased in the AV3V after, but not before, the onset of LPS fever, showing that the activity of the NO-cGMP pathway is reduced in the AV3V after intraperitoneal LPS, a mechanism that could contribute to the genesis and maintenance of fever. It was also observed that the efficacy of 8-BrcGMP in reducing Tc in the AVPO is increased after LPS, emphasizing that the NO-cGMP pathway is antipyretic. This response could explain why intra-AVPOl-NMMA enhanced the early stage of LPS fever, even though the activity of the NO pathway before the onset of fever was unchanged. In summary, these data support an antipyretic role of the NO-cGMP pathway in the AVPO.

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Cokic, Vladan P., Silvana A. Andric, Stanko S. Stojilkovic, Constance T. Noguchi, and Alan N. Schechter. "Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells." Blood 111, no. 3 (February 1, 2008): 1117–23. http://dx.doi.org/10.1182/blood-2007-05-088732.

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Abstract Hydroxyurea, a drug widely used for treating myeloproliferative diseases, has also been approved for the treatment of sickle cell disease by raising fetal hemoglobin (HbF). We have shown that nitric oxide (NO) and the soluble guanylyl cyclase (sGC) pathways are involved in hydroxyurea induction of HbF levels in erythroid progenitor cells (EPCs). We demonstrate now that during erythroid differentiation, endothelial NO synthase mRNA and protein levels decline steadily, as does the production of NO derivatives and cyclic adenosine monophosphate (cAMP) levels, but guanosine 3′,5′-cyclic monophosphate (cGMP) levels are stable. Hydroxyurea increased intracellular cGMP levels and cAMP levels in EPCs. The NO donor, DEANONOate, induced much higher cGMP levels, but reduced cAMP levels. Hydroxyurea (1 mM) induced production of approximately 45 pM cGMP/minute/ng of purified sGC, similar to induction by 1 μM DEANONOate. We found that hydroxyurea and ProliNONOate produced iron-nitrosyl derivatives of sGC. Thus, we confirm that hydroxyurea can directly interact with the deoxy-heme of sGC, presumably by a free-radical nitroxide pathway, and activate cGMP production. These data add to an expanding appreciation of the role of hydroxyurea as an inducer of the NO/cGMP pathway in EPCs. These mechanisms may also be involved in the cytostatic effects of hydroxyurea, as well as the induction of HbF.

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Li, Bo, Yanping Fu, Daohong Jiang, Jiatao Xie, Jiasen Cheng, Guoqing Li, Mahammad Imran Hamid, and Xianhong Yi. "Cyclic GMP as a Second Messenger in the Nitric Oxide-Mediated Conidiation of the Mycoparasite Coniothyrium minitans." Applied and Environmental Microbiology 76, no. 9 (March 5, 2010): 2830–36. http://dx.doi.org/10.1128/aem.02214-09.

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ABSTRACT Understanding signaling pathways that modulate conidiation of mitosporic fungi is of both practical and theoretical importance. The enzymatic origin of nitric oxide (NO) and its roles in conidiation by the sclerotial parasite Coniothyrium minitans were investigated. The activity of a nitric oxide synthase-like (NOS-like) enzyme was detected in C. minitans as evidenced by the conversion of l-arginine to l-citrulline. Guanylate cyclase (GC) activity was also detected indirectly in C. minitans with the GC-specific inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which significantly reduced production of cyclic GMP (cGMP). The dynamics of NOS activity were closely mirrored by the cGMP levels during pycnidial development, with the highest levels of both occurring at the pycnidial initiation stage of C. minitans. Furthermore, the NO donor, sodium nitroprusside (SNP), stimulated the accumulation of cGMP almost instantly in mycelium during the hyphal growth stage. When the activity of NOS or GC was inhibited with Nω-nitro-l-arginine or ODQ, conidial production of C. minitans was suppressed or completely eliminated; however, the suppression of conidiation by ODQ could be reversed by exogenous cGMP. The results also showed that conidiation of an l-arginine auxotroph could be restored by the NO donor SNP, but not by cGMP. Thus, NO-mediated conidiation has more than one signal pathway, including the cGMP signal pathway and another yet-unknown pathway, and both are essential for conidiation in C. minitans.

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Rengasamy, Appavoo, Thomas N. Pajewski, and Roger A. Johns. "Inhalational Anesthetic Effects on Rat Cerebellar Nitric Oxide and Cyclic Guanosine Monophosphate Production." Anesthesiology 86, no. 3 (March 1, 1997): 689–98. http://dx.doi.org/10.1097/00000542-199703000-00022.

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Background Inhalational anesthetics interact with the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway in the central nervous system (CNS) and attenuate excitatory neurotransmitter-induced cGMP concentration. The site of anesthetic action on the NO-cGMP pathway in the CNS remains controversial. This study investigated the effect of inhalational anesthetics on N-methyl-D-aspartate (NMDA)-stimulated NO synthase activity and cyclic cGMP production in rat cerebellum slices. Methods The interaction of inhalational anesthetics with NO synthase activation and cGMP concentration was determined in cerebellum slices of 10-day-old rats. Nitric oxide synthase activity in cerebellum slices was assessed by measuring the conversion of L-[3H]arginine to L-[3H]citrulline. The cGMP content of cerebellum slices was measured by radioimmunoassay. Results Isoflurane at 1.5% and 3% enhanced the NMDA-stimulated NO synthase activity by two times while halothane at 1.5% and 3% produced no significant effect. However, the NMDA-stimulated cGMP production was inhibited by both anesthetic agents. The anesthetic inhibition of cGMP accumulation was not significantly altered by a mixture of superoxide dismutase and catalase or by glycine, a coagonist of the NMDA receptor. Conclusions The enhancement of NMDA-induced NO synthase activity by isoflurane and the inhibition of NMDA-stimulated cGMP production by halothane and isoflurane suggests that inhalational anesthetics interfere with the neuronal NO-cGMP pathway. This inhibitory effect of anesthetics on cGMP accumulation is not due to either their interaction with the glycine binding site of the NMDA receptor or to the action of superoxide anions.

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Nalli, Ancy D., Sayak Bhattacharya, Hongxia Wang, Derek M. Kendig, John R. Grider, and Karnam S. Murthy. "Augmentation of cGMP/PKG pathway and colonic motility by hydrogen sulfide." American Journal of Physiology-Gastrointestinal and Liver Physiology 313, no. 4 (October 1, 2017): G330—G341. http://dx.doi.org/10.1152/ajpgi.00161.2017.

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Hydrogen sulfide (H2S), like nitric oxide (NO), causes smooth muscle relaxation, but unlike NO, does not stimulate soluble guanylyl cyclase (sGC) activity and generate cyclic guanosine 5′-monophosphate (cGMP). The aim of this study was to investigate the interplay between NO and H2S in colonic smooth muscle. In colonic smooth muscle from rabbit, mouse, and human, l-cysteine, substrate of cystathionine-γ-lyase (CSE), or NaHS, an H2S donor, inhibited phosphodiesterase 5 (PDE5) activity and augmented the increase in cGMP levels, IP3 receptor phosphorylation at Ser1756 (measured as a proxy for PKG activation), and muscle relaxation in response to NO donor S-nitrosoglutathione (GSNO), suggesting augmentation of cGMP/PKG pathway by H2S. The inhibitory effect of l-cysteine, but not NaHS, on PDE5 activity was blocked in cells transfected with CSE siRNA or treated with CSE inhibitor d,l-propargylglycine (dl-PPG), suggesting activation of CSE and generation of H2S in response to l-cysteine. H2S levels were increased in response to l-cysteine, and the effect of l-cysteine was augmented by GSNO in a cGMP-dependent protein kinase-sensitive manner, suggesting augmentation of CSE/H2S by cGMP/PKG pathway. As a result, GSNO-induced relaxation was inhibited by dl-PPG. In flat-sheet preparation of colon, l-cysteine augmented calcitonin gene-related peptide release in response to mucosal stimulation, and in intact segments, l-cysteine increased the velocity of pellet propulsion. These results demonstrate that in colonic smooth muscle, there is a novel interplay between NO and H2S. NO generates H2S via cGMP/PKG pathway, and H2S, in turn, inhibits PDE5 activity and augments NO-induced cGMP levels. In the intact colon, H2S promotes colonic transit. NEW & NOTEWORTHY Hydrogen sulfide (H2S) and nitric oxide (NO) are important regulators of gastrointestinal motility. The studies herein provide the cross talk between NO and H2S signaling to mediate smooth muscle relaxation and colonic transit. H2S inhibits phosphodiesterase 5 activity to augment cGMP levels in response to NO, which, in turn, via cGMP/PKG pathway, generates H2S. These studies suggest that interventions targeted at restoring NO and H2S homeostasis within the smooth muscle may provide novel therapeutic approaches to mitigate motility disorders.

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Danielewski, Oliver, Jan Schultess, and Albert Smolenski. "The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I." Thrombosis and Haemostasis 93, no. 02 (2005): 319–25. http://dx.doi.org/10.1160/th04-09-0582.

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SummaryThe NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined. We have studied NO/cGMP effects on the activity of Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp- 8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation. Thrombin-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G α i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin α IIbβ 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.

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Yang, Jin, John W. Clark, Robert M. Bryan, and Claudia S. Robertson. "Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth muscle cell." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 2 (August 2005): H886—H897. http://dx.doi.org/10.1152/ajpheart.00216.2004.

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The nitric oxide (NO)/cGMP pathway in the vascular smooth muscle cell (VSMC) is an important cellular signaling system for the regulation of VSMC relaxation. We present a mathematical model to investigate the underlying mechanisms of this pathway. The model describes the flow of NO-driven signal transduction: NO activation of soluble guanylate cyclase (sGC), sGC- and phosphodiesterase-catalyzed cGMP production and degradation, cGMP-mediated regulation of protein targets including the Ca2+-activated K+ (KCa) channel, and the myosin contractile system. Model simulations reproduce major NO/cGMP-induced VSMC relaxation effects, including intracellular Ca2+ concentration reduction and Ca2+ desensitization of myosin phosphorylation and force generation. Using the model, we examine several testable principles. 1) Rapid sGC desensitization is caused by end-product cGMP feedback inhibition; a large fraction of the steady-state sGC population is in an inactivated intermediate state, and cGMP production is limited well below maximum. 2) NO activates the KCa channel with both cGMP-dependent and -independent mechanisms; moderate NO concentration affects the KCa via the cGMP-dependent pathway, whereas higher NO concentration is accommodated by a cGMP-independent mechanism. 3) Chronic NO synthase inhibition may cause underexpressions of K+ channels including inward rectifier and KCa channels. 4) Ca2+ desensitization of the contractile system is distinguished from Ca2+ sensitivity of myosin phosphorylation. The model integrates these interactions among the heterogeneous components of the NO signaling system and can serve as a general modeling framework for studying NO-mediated VSMC relaxation under various physiological and pathological conditions. New data can be readily incorporated into this framework for interpretation and possible modification and improvement of the model.

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Perri, Roman E., Daniel A. Langer, Suvro Chatterjee, Simon J. Gibbons, Jay Gadgil, Sheng Cao, Gianrico Farrugia, and Vijay H. Shah. "Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 3 (March 2006): G535—G542. http://dx.doi.org/10.1152/ajpgi.00297.2005.

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NO antagonizes hepatic stellate cell (HSC) contraction, although activated HSC in cirrhosis demonstrate impaired responses to NO. Decreased NO responses in activated HSC and mechanisms by which NO affects activated HSC remain incompletely understood. In normal rat HSC, the NO donor diethylamine NONOate (DEAN) significantly increased cGMP production and reduced serum-induced contraction by 25%. The guanylate cyclase (sGC) inhibitor 1 H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one (ODQ) abolished 50% of DEAN effects, whereas the cGMP analog 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP) reiterated half the observed DEAN response, suggesting both cGMP-dependent protein kinase G (PKG)-dependent and -independent mechanisms of NO-mediated antagonism of normal HSC contraction. However, NO donors did not increase cGMP production from in vivo activated HSC from bile duct-ligated rats and showed alterations in intracellular Ca2+ accumulation suggesting defective cGMP-dependent effector pathways. The LX-2 cell line also demonstrated lack of cGMP generation in response to NO and a lack of effect of ODQ and 8-BrcGMP in modulating the NO response. However, cGMP-independent effects in response to NO were maintained in LX-2 and were associated with S-nitrosylation of proteins, an effect reiterated in primary HSC. Adenovirus-based overexpression of PKG significantly attenuated contraction of LX-2 by 25% in response to 8-BrcGMP. In summary, these studies demonstrate that NO affects HSC through cGMP-dependent and -independent pathways. The HSC activation process is associated with maintenance of cGMP-independent actions of NO but defects in cGMP-PKG-dependent NO signaling that are improved by PKG gene delivery in LX-2 cells. Activating targets downstream from NO-cGMP in activated HSC may represent a novel therapeutic target for portal hypertension.

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Wobst, Jana, Heribert Schunkert, and Thorsten Kessler. "Genetic alterations in the NO-cGMP pathway and cardiovascular risk." Nitric Oxide 76 (June 2018): 105–12. http://dx.doi.org/10.1016/j.niox.2018.03.019.

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Filice, E., T. Angelone, S. Imbrogno, D. Pellegrino, C. Adamo, A. Gattuso, and M. C. Cerra. "Beta3-adrenoceptors mediate negative lusitropism via NO-cGMP-PKG pathway." Journal of Molecular and Cellular Cardiology 42, no. 6 (June 2007): S25. http://dx.doi.org/10.1016/j.yjmcc.2007.03.071.

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Bailey, Kristina L., Joseph H. Sisson, Debra J. Romberger, James E. Robinson, and Todd A. Wyatt. "Alcohol Up-Regulates TLR2 Through a NO/cGMP Dependent Pathway." Alcoholism: Clinical and Experimental Research 34, no. 1 (January 2010): 51–56. http://dx.doi.org/10.1111/j.1530-0277.2009.01065.x.

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Golombek, Diego A., Patricia V. Agostino, Santiago A. Plano, and Gabriela A. Ferreyra. "Signaling in the mammalian circadian clock: the NO/cGMP pathway." Neurochemistry International 45, no. 6 (November 2004): 929–36. http://dx.doi.org/10.1016/j.neuint.2004.03.023.

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Signorello, Maria Grazia, Enrica Giacobbe, Mario Passalacqua, and Giuliana Leoncini. "The anandamide effect on NO/cGMP pathway in human platelets." Journal of Cellular Biochemistry 112, no. 3 (February 16, 2011): 924–32. http://dx.doi.org/10.1002/jcb.23008.

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Friebe, Andreas, Peter Sandner, and Achim Schmidtko. "cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development." Naunyn-Schmiedeberg's Archives of Pharmacology 393, no. 2 (December 18, 2019): 287–302. http://dx.doi.org/10.1007/s00210-019-01779-z.

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AbstractCyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC- and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the “9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications” held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

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Inamura, Kouhei, Makoto Kashiwayanagi, and Kenzo Kurihara. "Effects of cGMP and sodium nitroprusside on odor responses in turtle olfactory sensory neurons." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1201—C1206. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1201.

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The effects of cGMP and sodium nitroprusside (SNP) on odor responses in isolated turtle olfactory neurons were examined. The inward current induced by dialysis of a mixture of 1 mM cAMP and 1 mM cGMP was similar to that induced by dialysis of 1 mM cAMP or 1 mM cGMP alone. After the neurons were desensitized by the application of 1 mM cGMP, 3 mM 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, did not elicit any current, indicating that both cAMP and cGMP activated the same channel. Extracellular application of SNP, a nitric oxide (NO) donor, evoked inward currents in a dose-dependent manner. However, application of SNP did not induce any currents after desensitization of the cGMP-induced currents, suggesting that SNP-induced currents are mediated via the cGMP-dependent pathway. Application of the cAMP-producing odorants to the neurons induced a large inward current even after neurons were desensitized to a high concentration of cGMP or SNP. These results suggest that the transduction pathway independent of cAMP, cGMP, and NO also contributes to the generation of odor responses in addition to the cAMP-dependent pathway.

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Sato, Yoshikazu, Weixin Zhao, and George J. Christ. "Central modulation of the NO/cGMP pathway affects the MPOA-induced intracavernous pressure response." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 1 (July 1, 2001): R269—R278. http://dx.doi.org/10.1152/ajpregu.2001.281.1.r269.

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Alterations in the nitric oxide (NO)/cGMP levels in hypothalamic nuclei, including the medial preoptic area (MPOA), regulate critical aspects of sexual behavior and penile reflexes. However, the effects of altered central nervous system (CNS) NO/cGMP levels at the end organ level, that is, on the magnitude/quality of the erection so achieved [intracavernous pressure (ICP) response], has yet to be evaluated. The goal of this report was to evaluate the effects of intrathecal administration of modulators of NO and cGMP levels on ICP responses to stimulation of the MPOA and cavernous nerve in rats in vivo. In all cases, intrathecal administration of compounds that increase and decrease cGMP and NO levels, respectively, was associated with corresponding increases and decreases in the MPOA-stimulated ICP response. Specifically, sodium nitroprusside (SNP), 8-bromo-cGMP, and sildenafil increased the MPOA-stimulated ICP response, whereas N ω-nitro-l-arginine methyl ester reduced it. None of the intrathecal treatments had detectable effects on blood pressure or the cavernous nerve-stimulated ICP response, although intravenous sildenafil increased the latter. These data clearly indicate that intrathecal drug administration affects central and not peripheral neural mechanisms and, moreover, documents that CNS NO/cGMP levels can affect erectile capacity per se (i.e., ICP) in the rat model.

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BLOM, JAN J., TODD A. BLUTE, and WILLIAM D. ELDRED. "Functional localization of the nitric oxide/cGMP pathway in the salamander retina." Visual Neuroscience 26, no. 3 (May 2009): 275–86. http://dx.doi.org/10.1017/s0952523809990125.

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AbstractNitric oxide (NO) is a gaseous neuromodulator that has physiological functions in every cell type in the retina. Evidence indicates that NO often plays a role in the processing of visual information in the retina through the second messenger cyclic guanosine monophosphate (cGMP). Despite numerous structural and functional studies of this signaling pathway in the retina, none have examined many of the elements of this pathway within a single study in a single species. In this study, the NO/cGMP pathway was localized to specific regions and cell types within the inner and outer retina. We have immunocytochemically localized nitric oxide synthase, the enzyme that produces NO, in photoreceptor ellipsoids, four distinct classes of amacrine cells, Müller and bipolar cells, somata in the ganglion cell layer, as well as in processes within both plexiform layers. Additionally, we localized NO production in specific cell types using the NO-sensitive dye diaminofluorescein. cGMP immunocytochemistry was used to functionally localize soluble guanylate cyclase that was activated by an NO donor in select amacrine and bipolar cell classes. Analysis of cGMP and its downstream target, cGMP-dependent protein kinase II (PKGII), showed colocalization within processes in the outer retina as well as in somata in the inner retina. The results of this study showed that the NO/cGMP signaling pathway was functional and its components were widely distributed throughout specific cell types in the outer and inner salamander retina.

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Liu, Fuhe, Wenjuan Ni, Jiajia Zhang, Guokang Wang, Fanzhu Li, and Wenxia Ren. "Administration of Curcumin Protects Kidney Tubules Against Renal Ischemia-Reperfusion Injury (RIRI) by Modulating Nitric Oxide (NO) Signaling Pathway." Cellular Physiology and Biochemistry 44, no. 1 (2017): 401–11. http://dx.doi.org/10.1159/000484920.

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Background/Aims: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue’s NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. Methods: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups’ β2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups’ nephridial histomorphology and kidney tubules score were evaluated and compared. Results: β2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. Conclusion: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.

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Schachter, David, and James C. Sang. "Aortic leucine-to-glutamate pathway: metabolic route and regulation of contractile responses." American Journal of Physiology-Heart and Circulatory Physiology 282, no. 3 (March 1, 2002): H1135—H1148. http://dx.doi.org/10.1152/ajpheart.00457.2001.

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Rat aortic endothelium is differentiated regionally for three signal pathways capable of regulating the cGMP content of the underlying smooth muscle. Formation of nitric oxide (NO) from l-arginine and of glutamate from l-leucine increase cGMP; however, formation of prostaglandin H2(PGH2) decreases cGMP. All three have peak activity in the windkessel area just distal to the aortic arch and decrease peripherally. We report evidence that the biochemical route of the leucine-to-glutamate (Leu→Glu) pathway is via metabolism of leucine to acetyl CoA, that the controlling reaction of the pathway is mediated by the branched chain α-ketoacid dehydrogenase complex (BCDC), and that glutamate formation via the Leu→Glu pathway is a major source of aortic segment free glutamate in vitro. Interruption of the pathway by treatment of precontracted rat aortic rings in vitro with each of three classes of inhibitors (leucine analogs, competitors for the BCDC reaction, or inhibitors of l-glutamate transport) enhances contractile responses. The enhancement requires an intact endothelium and is not owing to reductions in NO formation. The results support the hypothesis that the Leu→Glu pathway functions in the regulation of aortic contractility and compliance.

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Russo, I., P. Del Mese, G. Doronzo, L. Mattiello, M. Viretto, A. Bosia, G. Anfossi, and M. Trovati. "Resistance to the Nitric Oxide/Cyclic Guanosine 5′-Monophosphate/Protein Kinase G Pathway in Vascular Smooth Muscle Cells from the Obese Zucker Rat, a Classical Animal Model of Insulin Resistance: Role of Oxidative Stress." Endocrinology 149, no. 4 (December 13, 2007): 1480–89. http://dx.doi.org/10.1210/en.2007-0920.

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Some in vivo and ex vivo studies demonstrated a resistance to the vasodilating effects of nitric oxide (NO) in insulin-resistant states and, in particular, obese Zucker rats (OZR). To evaluate the biochemical basis of this phenomenon, we aimed to identify defects of the NO/cGMP/cGMP-dependent protein kinase (PKG) pathway in cultured vascular smooth muscle cells (VSMCs) from OZR and lean Zucker rats (LZR) by measuring: 1) NO donor ability to increase cGMP in the absence and presence of inhibitors of soluble guanylate cyclase (sGC) and phosphodiesterases (PDEs); 2) NO and cGMP ability to induce, via PKG, vasodilator-stimulated phosphoprotein (VASP) phosphorylation at serine 239 and PDE5 activity; 3) protein expression of sGC, PKG, total VASP, and PDE5; 4) superoxide anion concentrations and ability of antioxidants (superoxide dismutase+catalase and amifostine) to influence the NO/cGMP/PKG pathway activation; and 5) hydrogen peroxide influence on PDE5 activity and VASP phosphorylation. VSMCs from OZR vs. LZR showed: 1) baseline cGMP concentrations higher, at least in part owing to reduced catabolism by PDEs; 2) impairment of NO donor ability to increase cGMP, even in the presence of PDE inhibitors, suggesting a defect in the NO-induced sGC activation; 3) reduction of NO and cGMP ability to activate PKG, indicated by the impaired ability to phosphorylate VASP at serine 239 and to increase PDE5 activity via PKG; 4) similar baseline protein expression of sGC, PKG, total VASP, and PDE5; and 5) higher levels of superoxide anion. Antioxidants partially prevented the defects of the NO/cGMP/PKG pathway observed in VSMCs from OZR, which were reproduced by hydrogen peroxide in VSMCs from LZR, suggesting the pivotal role of oxidative stress.

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Seidel, C., and G. Bicker. "Nitric oxide and cGMP influence axonogenesis of antennal pioneer neurons." Development 127, no. 21 (November 1, 2000): 4541–49. http://dx.doi.org/10.1242/dev.127.21.4541.

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The grasshopper embryo has been used as a convenient system with which to investigate mechanisms of axonal navigation and pathway formation at the level of individual nerve cells. Here, we focus on the developing antenna of the grasshopper embryo (Schistocerca gregaria) where two siblings of pioneer neurons establish the first two axonal pathways to the CNS. Using immunocytochemistry we detected nitric oxide (NO)-induced synthesis of cGMP in the pioneer neurons of the embryonic antenna. A potential source of NO are NADPH-diaphorase-stained epithelial cells close to the basal lamina. To investigate the role of the NO/cGMP signaling system during pathfinding, we examined the pattern of outgrowing pioneer neurons in embryo culture. Pharmacological inhibition of soluble guanylyl cyclase (sGC) and of NO synthase (NOS) resulted in an abnormal pattern of pathway formation in the antenna. Axonogenesis of both pairs of pioneers was inhibited when specific NOS or sGC inhibitors were added to the culture medium; the observed effects include the loss axon emergence as well as retardation of outgrowth, such that growth cones do not reach the CNS. The addition of membrane-permeant cGMP or a direct activator of the sGC enzyme to the culture medium completely rescued the phenotype resulting from the block of NO/cGMP signaling. These results indicate that NO/cGMP signaling is involved in axonal elongation of pioneer neurons in the antenna of the grasshopper.

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Tao, Yuan-Xiang, Aalya Hassan, and Roger A. Johns. "Intrathecally Administered cGMP-dependent Protein Kinase Iα Inhibitor Significantly Reduced the Threshold for Isoflurane Anesthesia." Anesthesiology 92, no. 2 (February 1, 2000): 493. http://dx.doi.org/10.1097/00000542-200002000-00032.

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Background Inhalational anesthetics have been shown to inhibit the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Previous studies indicated that inhibition of the NO-cGMP pathway decreased the level of consciousness and augmented anesthesia, analgesia, or sedation. The current study investigated the possible involvement of cGMP-dependent protein kinases (PKGs) as major effectors for the NO-cGMP pathway in the anesthetic state. Methods After initial baseline determination of the minimum alveolar concentration (MAC), a selective cGMP-dependent protein kinase Ialpha inhibitor, Rp-8-p-CPT-cGMPS, or an NO donor, (NOC-12), were injected intrathecally. Ten minutes later, MAC measurement was repeated. The rats also were evaluated for the presence of locomotor dysfunction by intrathecal administration of Rp-8-p-CPT-cGMPS and NOC-12 in conscious rats. Results Rp-8-p-CPT-cGMPS at 25, 50, 100, and 200 microg/10 microl produced a significant decrease from isoflurane control MAC of -4+/-3.1%, 16+/-4.5%, 30+/-5.0%, and 21+/-2.2%, respectively, which was not accompanied by significant changes in either blood pressure or heart rate. In contrast, NOC-12 at 100 microg/10 microl caused an increase from isoflurane control MAC of 23+/-5.8%, which was accompanied by significant decrease in blood pressure but not in heart rate. Rp-8-p-CPT-cGMPS (100 microg/10 microl) produced a significant reversal of isoflurane MAC increase induced by NOC-12 (100 microg/10 microl), which was accompanied by significant reversal of the reduction of blood pressure induced by NOC-12. Locomotor activity was not changed. Conclusions The results indicate that cGMP-dependent protein kinase Ialpha inhibitor not only markedly reduces MAC for isoflurane, but also completely blocks the NO-induced increase in isoflurane MAC, which suggests that cGMP-dependent protein kinase Ialpha may mediate the action for the NO-cGMP pathway in anesthetic mechanisms at the spinal cord level.

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Elrod, John W., James J. M. Greer, and David J. Lefer. "Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 1 (January 2007): H342—H347. http://dx.doi.org/10.1152/ajpheart.00306.2006.

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Sildenafil, a potent inhibitor of phosphodiesterase type 5, has recently been investigated in animal models of myocardial ischemia-reperfusion (MI/R) injury. Previous studies have suggested that the protective effects of sildenafil are mediated via activation of endothelial nitric oxide (NO) synthesis (eNOS) and inducible NOS (iNOS). To further investigate the protective mechanism of sildenafil, we subjected wild-type, eNOS, and iNOS null animals to 30 min of myocardial ischemia and 24 h of reperfusion. Treatment with 0.06 mg/kg sildenafil 5 min before reperfusion significantly reduced myocardial infarct size in wild-type, eNOS null mice (eNOS−/−), and iNOS−/− animals. Additionally, the low dose utilized in this study did not alter myocardial cGMP. These results suggest that acute low-dose sildenafil-mediated cardioprotection is independent of eNOS, iNOS, and cGMP. In a second series of experiments, we investigated sildenafil in db/ db diabetic mice subjected to MI/R. We found that sildenafil failed to protect diabetic mice against MI/R. However, NO· donor therapy was found to significantly protect against MI/R injury in both nondiabetic and diabetic mice, suggesting that protection could be conferred in diabetic mice and that the upstream modulator of soluble guanylyl cyclase, NO·, may mediate protection independent of cGMP signaling. The present study suggests that further research is needed to delineate the precise mechanisms by which sildenafil exerts cardioprotection.

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Ellis, Dorette Z., James A. Nathanson, and Kathleen J. Sweadner. "Carbachol inhibits Na+-K+-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway." American Journal of Physiology-Cell Physiology 279, no. 6 (December 1, 2000): C1685—C1693. http://dx.doi.org/10.1152/ajpcell.2000.279.6.c1685.

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Secretion of cerebrospinal fluid by the choroid plexus can be inhibited by its cholinergic innervation. We demonstrated that carbachol inhibits the Na+-K+-ATPase in bovine choroid tissue slices and investigated the mechanism. Many of the actions of cholinergic agents are mediated by nitric oxide (NO), which plays important roles in fluid homeostasis. The inhibition of Na+-K+-ATPase was blocked by the NO synthase inhibitor [ N ω-nitro-L-arginine methyl ester] and was quantitatively mimicked by the NO agonists sodium nitroprusside (SNP) and diethylenetriamine NO. Inhibition by SNP correlated with an increase in tissue cGMP and was abolished by 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5–5 μM) and KT-5823 (2.0 μM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na+-K+-ATPase. The data suggest that cholinergic regulation of the Na+-K+-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP.

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Miraglia, Erica, Federico De Angelis, Elena Gazzano, Hossain Hassanpour, Angela Bertagna, Elisabetta Aldieri, Alberto Revelli, and Dario Ghigo. "Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway." REPRODUCTION 141, no. 1 (January 2011): 47–54. http://dx.doi.org/10.1530/rep-10-0151.

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Nitric oxide (NO), a modulator of several physiological processes, is involved in different human sperm functions. We have investigated whether NO may stimulate the motility of human spermatozoa via activation of the soluble guanylate cyclase (sGC)/cGMP pathway. Sperm samples obtained by masturbation from 70 normozoospermic patients were processed by the swim-up technique. The kinetic parameters of the motile sperm-rich fractions were assessed by computer-assisted sperm analysis. After a 30–90 min incubation, the NO donor S-nitrosoglutathione (GSNO) exerted a significant enhancing effect on progressive motility (77, 78, and 78% vs 66, 65, and 62% of the control at the corresponding time), straight linear velocity (44, 49, and 48 μm/s vs 34, 35, and 35.5 μm/s), curvilinear velocity (81, 83, and 84 μm/s vs 68 μm/s), and average path velocity (52, 57, and 54 μm/s vs 40, 42, and 42 μm/s) at 5 μM but not at lower concentrations, and in parallel increased the synthesis of cGMP. A similar effect was obtained with the NO donor spermine NONOate after 30 and 60 min. The GSNO-induced effects on sperm motility were abolished by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (a specific sGC inhibitor) and mimicked by 8-bromo-cGMP (8-Br-cGMP; a cell-permeating cGMP analog); the treatment with Rp-8-Br-cGMPS (an inhibitor of cGMP-dependent protein kinases) prevented both the GSNO- and the 8-Br-cGMP-induced responses. On the contrary, we did not observe any effect of the cGMP/PRKG1 (PKG) pathway modulators on the onset of hyperactivated sperm motility. Our results suggest that NO stimulates human sperm motility via the activation of sGC, the subsequent synthesis of cGMP, and the activation of cGMP-dependent protein kinases.

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Shahpar, Salehi, Ilkhanipour Minoo Minoo, Nejati Vahid, and Sadeghi-Hashjin Goudarz. "Physiological Effects of NO-cGMP Pathway on Ovarian Steroidogenesis in Rat." Pakistan Journal of Biological Sciences 10, no. 8 (April 1, 2007): 1175–79. http://dx.doi.org/10.3923/pjbs.2007.1175.1179.

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Foroutan, Arash, Nazgol Sadat Haddadi, Sattar Ostadhadi, Narges Sistany, and Ahmad Reza Dehpour. "Chloroquine-induced scratching is mediated by NO/cGMP pathway in mice." Pharmacology Biochemistry and Behavior 134 (July 2015): 79–84. http://dx.doi.org/10.1016/j.pbb.2015.04.016.

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Fedele, Ernesto, and Maurizio Raiteri. "In vivo studies of the cerebral glutamate receptor/NO/cGMP pathway." Progress in Neurobiology 58, no. 1 (June 1999): 89–120. http://dx.doi.org/10.1016/s0301-0082(98)00077-x.

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Felipo, Vicente. "Methylmercury during development impairs the glutamate-NO-cGMP pathway and learning." Toxicology Letters 211 (June 2012): S7. http://dx.doi.org/10.1016/j.toxlet.2012.03.037.

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Deruelle, Philippe, Alexandre Ceneric, Veronique Debarge, Estelle Aubry, and Laurent Storme. "Regulation of the feto-placental circulation by the NO-cGMP pathway." American Journal of Obstetrics and Gynecology 195, no. 6 (December 2006): S113. http://dx.doi.org/10.1016/j.ajog.2006.10.380.

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Figueroa, Xavier F., Inés Poblete, Ricardo Fernández, Cristóbal Pedemonte, Víctor Cortés, and J. Pablo Huidobro-Toro. "NO production and eNOS phosphorylation induced by epinephrine through the activation of β-adrenoceptors." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 1 (July 2009): H134—H143. http://dx.doi.org/10.1152/ajpheart.00023.2009.

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Epinephrine plays a key role in the control of vasomotor tone; however, the participation of the NO/cGMP pathway in response to β-adrenoceptor activation remains controversial. To evaluate the involvement of the endothelium in the vascular response to epinephrine, we assessed NO production, endothelial NO synthase phosphorylation, and tissue accumulation of cGMP in the perfused arterial mesenteric bed of rat. Epinephrine elicited a concentration-dependent increase in NO (EC50 of 45.7 pM), which was coupled to cGMP tissue accumulation. Both NO and cGMP production were blocked by either endothelium removal (saponin) or NO synthase inhibition ( Nω-nitro-l-arginine). Blockade of β1- and β2-adrenoceptors with 1 μM propranolol or β3-adrenoceptor with 10 nM SR 59230A displaced rightward the concentration-NO production curve evoked by epinephrine. Selective stimulation of β1-, β2-, or β3-adrenoceptors also resulted in NO and cGMP production. Propranolol (1 μM) inhibited the rise in NO induced by isoproterenol or the β2-adrenoceptor agonists salbutamol, terbutaline, or fenoterol. Likewise, 10 nM SR 59230A reduced the effects of the β3-adrenoceptor agonists BRL 37344, CGP 12177, SR 595611A, or pindolol. The NO production induced by epinephrine and BRL 37344 was associated with the activation of the phosphatidylinositol 3-kinase/Akt pathway and phosphorylation of eNOS in serine 1177. In addition, in anaesthetized rats, bolus administration of isoproterenol, salbutamol, or BRL 37344 produced NO-dependent reductions in systolic blood pressure. These findings indicate that β1-, β2-, and β3-adrenoceptors are coupled to the NO/cGMP pathway, highlighting the role of the endothelium in the vasomotor action elicited by epinephrine and related β-adrenoceptor agonists.

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Kurtz, Armin, Karl-Heinz Götz, Marlies Hamann, Martin Kieninger, and Charlotte Wagner. "Stimulation of renin secretion by NO donors is related to the cAMP pathway." American Journal of Physiology-Renal Physiology 274, no. 4 (April 1, 1998): F709—F717. http://dx.doi.org/10.1152/ajprenal.1998.274.4.f709.

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This study aimed to characterize the cellular pathways along which nitric oxide (NO) influences the secretion of renin from the kidney. Using the isolated perfused rat kidney model, we found that the NO donor sodium nitroprusside (SNP) (1–30 μmol/l) induced a prompt, concentration-dependent fourfold increase of basal renin secretion. The membrane-permeable cGMP analogs 8-bromo-cGMP and 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP; each 5–50 μmol/l) inhibited basal renin secretion and attenuated the stimulation of renin secretion by SNP. Conversely, the renin stimulatory effect of SNP was enhanced in the presence of the G kinase inhibitor Rp-8-CPT-cGMPS (10 μmol/l). The renin stimulatory effect of SNP was amplified in nominally calcium-free perfusate and was abolished in the presence of angiotensin II (1 nmol/l). Renin secretion stimulated by SNP was clearly attenuated by the A kinase inhibitor Rp-8-CPT-cAMPS (25 μmol/l). These findings indicate that the renin stimulatory effect of NO donors in renal juxtaglomerular cells cannot be explained by activation of G kinase and is also less likely to be causally related to the regulation of renin secretion by calcium. Because A kinase activity is required for the stimulation of renin secretion by SNP, it appears as if the renin stimulatory effect is causally related to the cAMP pathway controlling renin secretion.

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Hansen, JM, LL Thomsen, J. Olesen, and M. Ashina. "Familial Hemiplegic Migraine Type 1 Shows no Hypersensitivity to Nitric Oxide." Cephalalgia 28, no. 5 (May 2008): 496–505. http://dx.doi.org/10.1111/j.1468-2982.2008.01559.x.

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Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 μg kg−1 min−1 glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (VmeanMCA) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUCheadache in the immediate phase was more pronounced in patients than in controls ( P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUCheadache between patients and controls ( P = 0.17). We found no difference in the AUCVmeanMCA ( P = 0.12) or AUCSTA ( P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.

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Basini, G., F. Grasselli, N. Ponderato, S. Bussolati, and C. Tamanini. "Lipid hydroperoxide and cGMP are not involved in nitric oxide inhibition of steroidogenesis in bovine granulosa cells." Reproduction, Fertility and Development 12, no. 6 (2000): 289. http://dx.doi.org/10.1071/rd00089.

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The present study was performed to explore two of the possible signalling mechanisms through which nitric oxide (NO) inhibits steroidogenesis in bovine granulosa cells. Because cGMP is generally known to play a pivotal role in NO signal transduction, the first aim of the present study was to verify the presence of a functional NO–cGMP signalling pathway. Because non-cGMP-dependent pathways could be involved in the inhibition of steroidogenesis by NO, we examined the formation of lipid hydroperoxides (LPOs), possibly induced by NO. Using bovine granulosa cells collected from small (< 5 mm) and large (> 8 mm) follicles, the effectiveness of the NO donor s-nitroso-N-acetylpenicillamine (SNAP; 10–3, 10–4 and 10–5 M) in stimulating cGMP production and the formation of LPOs was examined. The second aim of the present study was to determine whether the effects of NO on steroidogenesis could be mimicked by treatment of cells with a cGMP analogue (8-bromo-cGMP (8-Br-cGMP); 10–3, 10–4 and 10–5 M) and whether these effects could be reversed by [1H]-[1,2,3]oxadiaziolo[4,3a]quinoxaline-1-one (ODQ; 10–5 and 10–4 M) an inhibitor of NO-sensitive soluble guanylate cyclase. The highest dose of SNAP used induced a significant (P<0.01) increase in cGMP levels, while other concentrations tested were ineffective. Neither concentration of ODQ used significantly inhibited basal cGMP output, while both concentrations counteracted the stimulatory effect of SNAP. Treatment of cells with 8-Br-cGMP and ODQ was ineffective in modifying steroidogenesis. Treatment with SNAP, at the three concentrations tested, had no significant effect on the level of LPOs. The present results suggest that NO inhibits steroidogenesis in bovine granulosa cells without involving cGMP and LPOs.

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Fessenden, James D., and Jochen Schacht. "Localization of Soluble Guanylate Cyclase Activity in the Guinea Pig Cochlea Suggests Involvement in Regulation of Blood Flow and Supporting Cell Physiology." Journal of Histochemistry & Cytochemistry 45, no. 10 (October 1997): 1401–8. http://dx.doi.org/10.1177/002215549704501008.

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Although the nitric oxide/cGMP pathway has many important roles in biology, studies of this system in the mammalian cochlea have focused on the first enzyme in the pathway, nitric oxide synthase (NOS). However, characterization of the NO receptor, soluble guanylate cyclase (sGC), is crucial to determine the cells targeted by NO and to develop rational hypotheses of the function of this pathway in auditory processing. In this study we characterized guinea pig cochlear sGC by determining its enzymatic activity and cellular localization. In cytosolic fractions of auditory nerve, lateral wall tissues, and co-chlear neuroepithelium, addition of NO donors resulted in three- to 15-fold increases in cGMP formation. NO-stimulated sGC activity was not detected in particulate fractions. We also localized cochlear sGC activity through immunocytochemical detection of NO-stimulated cGMP. sGC activity was detected in Hensen's and Deiters' cells of the organ of Corti, as well as in vascular pericytes surrounding small capillaries in the lateral wall tissues and sensory neuroepithelium. sGC activity was not observed in sensory cells. Using NADPH-diaphorase histochemistry, NOS was localized to pillar cells and nerve fibers underlying hair cells. These results indicate that the NO/cGMP pathway may influence diverse elements of the auditory system, including cochlear blood flow and supporting cell physiology.

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CAO, LUXIANG, TODD A. BLUTE, and WILLIAM D. ELDRED. "Localization of heme oxygenase-2 and modulation of cGMP levels by carbon monoxide and/or nitric oxide in the retina." Visual Neuroscience 17, no. 3 (May 2000): 319–29. http://dx.doi.org/10.1017/s0952523800173018.

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Heme oxygenase-2 (HO-2) synthesizes carbon monoxide (CO), a modulator of soluble guanylate cyclase (sGC). To examine this signal transduction pathway in the retina, we immunocytochemically localized HO-2, and investigated the effects of CO on cGMP levels. In turtle, HO-2-like immunoreactivity (-LI) was in all photoreceptors, some amacrine cells, and in numerous bipolar and ganglion cells. HO-2-LI colocalized with sGC activity in many cells. In rat, HO-LI was found only in the inner retina, in ganglion and amacrine cells. In turtle, stimulation with CO alone primarily increased cGMP-LI in bipolar cells in the visual streak. Stimulation with a combination of CO and nitric oxide (NO) dramatically increased cGMP-LI throughout the retina, in comparison to the smaller increases seen with NO or CO alone. These data suggest that CO is an endogenous modulator of the sGC/cGMP signaling pathway in many retinal neurons, and can dramatically amplify NO-stimulated increases in cGMP.

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Edwards, R. M., M. Pullen, and P. Nambi. "Activation of endothelin ETB receptors increases glomerular cGMP via an L-arginine-dependent pathway." American Journal of Physiology-Renal Physiology 263, no. 6 (December 1, 1992): F1020—F1025. http://dx.doi.org/10.1152/ajprenal.1992.263.6.f1020.

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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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Thoonen, Robrecht, Manu Buys, Patrick Sips, Elke Rogge, Tino Hochepied, Sofie Nimmegeers, Johan Van de Voorde, and Peter Brouckaert. "O54. Targeting the NO-cGMP pathway: Phenotyping of NO-insensitive sGCβ1 H105F knockin mice." Nitric Oxide 19 (2008): 32. http://dx.doi.org/10.1016/j.niox.2008.06.055.

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Kawamata, Tomoyuki, and Keiichi Omote. "Activation of Spinal N-methyl-D-aspartate Receptors Stimulates a Nitric Oxide/Cyclic Guanosine 3′,5′-monophosphate/Glutamate Release Cascade in Nociceptive Signaling." Anesthesiology 91, no. 5 (November 1, 1999): 1415. http://dx.doi.org/10.1097/00000542-199911000-00035.

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Background Increasing evidence has suggested the possibility that the activation of N-methyl-D-aspartate (NMDA) receptors modulates spinal nociceptive transmission via a nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. However, the existence and the role of an NO/cGMP pathway in the modulation of spinal nociceptive transmission has been unclear. The authors hypothesized that the activation of NMDA receptors stimulates an NO/cGMP pathway, and this pathway evokes glutamate release within the spinal cord, modulating spinal nociceptive transmission. Methods The authors have examined the effects of an NO synthase inhibitor and a soluble guanylate cyclase inhibitor on the concentrations of NO metabolites (NO2-/NO3-) and glutamate in the cerebrospinal fluid after intrathecal perfusion of NMDA, concomitantly observing pain-related behavior (scratching, biting, and vocalization) in unanesthetized, free-moving rats using an intrathecal microdialysis method. The contents of cGMP in the dorsal horn were also measured using enzyme immunoassay method. Results Intrathecal perfusion of NMDA produced pain-related behavior and increased glutamate and NO2-/NO3-concentrations in a dose-dependent manner. A competitive NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid, completely blocked the NMDA-induced responses. An NO synthase inhibitor, N(G)-monomethyl-L-arginine acetate, at a dose that completely blocked the increase in NO2-/NO3-, inhibited both the NMDA-induced pain-related behavior and the increase in glutamate concentration. In addition, a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one, also inhibited significantly NMDA-induced pain-related behavior and the increase in glutamate concentration. NMDA induced an increase in cGMP in the dorsal half of the spinal cord, which was blocked by N(G)-monomethyl-L-arginine acetate. Conclusions The results of this study support the hypothesis that the activation of NMDA receptors modulated pain-related behavior via an NO/cGMP/glutamate release cascade within the spinal cord.

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Li, Li-sheng, Yun-mei Luo, Juan Liu, Yu Zhang, Xiao-xia Fu, and Dan-li Yang. "Icariin Inhibits Pulmonary Hypertension Induced by Monocrotaline through Enhancement of NO/cGMP Signaling Pathway in Rats." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/7915415.

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It has been reported that icariin (ICA) increased contents of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) by improving expression of endothelial nitric oxide synthase (eNOS) and inhibition of phosphodiesterase type 5 (PDE5). In addition, dysfunction of the NO/cGMP pathway may play a crucial role in the pathogenesis of pulmonary hypertension (PH). In this study, the potential protective effects of ICA on PH induced by monocrotaline (MCT, 50 mg/kg) singly subcutaneous injection were investigated and the possible mechanisms involved in NO/cGMP pathway were explored in male Sprague Dawley rats. The results showed that ICA (20, 40, and 80 mg/kg/d) treatment by intragastric administration could significantly ameliorate PH and upregulate the expression of eNOS gene and downregulate the expression of PDE5 gene in MCT-treated rats. Both ICA (40 mg/kg/d) and L-arginine (200 mg/kg/d), a precursor of NO as positive control, notably increased the contents of NO and cGMP in lung tissue homogenate, which were inversed by treatment withGN-nitro-L-arginine-methyl ester (L-NAME), a NOS inhibitor, and L-NAME-treatment could also inhibit the protective effects of ICA (40 mg/kg/d) on mean pulmonary artery pressure and artery remodeling and tends to inhibit right ventricle hypertrophy index. In summary, ICA is effective in protecting against MCT-induced PH in rats through enhancement of NO/cGMP signaling pathway in rats.

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Journal articles on the topic 'NO-cGMP pathway'

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