Activation of Spinal N-methyl-D-aspartate Receptors Stimulates a Nitric Oxide/Cyclic Guanosine 3′,5′-monophosphate/Glutamate Release Cascade in Nociceptive Signaling 

1999 ◽  
Vol 91 (5) ◽  
pp. 1415-1415 ◽  
Author(s):  
Tomoyuki Kawamata ◽  
Keiichi Omote
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Nmda Receptors ◽  
Soluble Guanylate Cyclase ◽  
Glutamate Release ◽  
No Synthase ◽  
Nociceptive Transmission ◽  
Glutamate Concentration ◽  
Cgmp Pathway ◽  
Synthase Inhibitor

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.

Relationship between nitric oxide and opioids in hypoxia-induced pial artery vasodilation

1996 ◽  
Vol 270 (3) ◽  
pp. H869-H874 ◽  
Author(s):  
M. J. Wilderman ◽  
W. M. Armstead
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
No Synthase ◽  
Pial Artery ◽  
Biochemical Effects ◽  
M 10 ◽  
Before And After ◽  
Synthase Inhibitor ◽  
Ly 83583 ◽  
The Relationship

It has previously been observed that nitric oxide (NO) and the opioids Met- and Leu-enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. The present study was designed to investigate the relationship between NO and opioids in hypoxic pial dilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids. Sodium nitroprusside (SNP; 10(-8) and 10(-6) M) elicited pial dilation that was blunted by the soluble guanylate cyclase inhibitor LY-83583 (10(-5) M; 10 +/- 1 and 23 +/- 1 vs. 3 +/- 1 and 7 +/- 1% for 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced dilation was accompanied by increased CSF Met-enkephalin, and coadministration of LY-83583 with SNP blocked these increases in CSF opioid concentration (1,144 +/- 59, 2,215 +/- 165, and 3,413 +/- 168 vs. 1,023 +/- 16, 1,040 +/- 18, and 1,059 +/- 29 pg/ml for control and 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced release of CSF Leuenkephalin was also blocked by LY-83583. Similar blunted vascular and biochemical effects of SNP were observed with coadministration of the purported guanosine 3', 5'-cyclic monophosphate (cGMP) antagonist, the phosphorothioate analogue of 8-bromo-cGMP (BrcGMP) [(R)-p-BrcGMP[S]; 10(-5) M]. The cGMP analogue, BrcGMP, elicited dilation that was also accompanied by increased CSF Met- and Leu-enkephalin. Vascular and biochemical effects of BrcGMP were blunted by (R)-p-cGMP[S] and unchanged by LY-83583. Hypoxia-induced pial artery dilation was attenuated by N omega-nitro-L-arginine (L-NNA; 10(-6) M), an NO synthase inhibitor (25 +/- 2 vs. 14 +/- 1%). Hypoxic pial dilation was accompanied by increased CSF Met-enkephalin, and these increases were attenuated by L-NNA (1,137 +/- 60 and 3,491 +/- 133 vs. 927 +/- 25 and 2,052 +/- 160 pg/ml for control and hypoxia before and after L-NNA, respectively). Hypoxia also increased CSF Leuenkephalin, and these CSF changes were similarly attenuated by L-NNA. These data show that cGMP increases CSF Met- and Leu-enkephalin. Furthermore, these data suggest that NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.

Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors

Nitric Oxide ◽  
2007 ◽  
Vol 17 (1) ◽  
pp. 18-24 ◽  
Author(s):  
Li Xu ◽  
Tamaki Mabuchi ◽  
Tayo Katano ◽  
Shinji Matsumura ◽  
Emiko Okuda-Ashitaka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Nmda Receptors ◽  
No Synthase ◽  
Neuronal No Synthase ◽  
Retrograde Messenger

Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules

2002 ◽  
Vol 282 (3) ◽  
pp. H1111-H1117 ◽  
Author(s):  
Wolfgang H. Cerwinka ◽  
Dianne Cooper ◽  
Christian F. Krieglstein ◽  
Martin Feelisch ◽  
D. Neil Granger
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Soluble Guanylate Cyclase ◽  
Vascular Diseases ◽  
Fold Increase ◽  
No Synthase ◽  
No Donor ◽  
Platelet Endothelial Cell Adhesion ◽  
Adhesive Interactions ◽  
Synthase Inhibitor

Although platelets have been implicated in the pathogenesis of vascular diseases, little is known about factors that regulate interactions between platelets and the vessel wall under physiological conditions. The objectives of this study were to 1) define the contribution of nitric oxide (NO) to endotoxin (lipopolysaccharide, LPS)-induced platelet-endothelial cell (P/E) adhesion in murine intestinal venules and 2) determine whether the antiadhesive action of NO is mediated by soluble guanylate cyclase (sGC). Adhesive interactions between platelets and endothelial cells were monitored by intravital microscopy. LPS administration into control wild-type mice (WT) resulted in a >15-fold increase in P/E adhesion. Similar responses were observed using endothelial NO synthase (eNOS)-deficient platelets. However, treatment with the NO donor diethylenetriamine-nitric oxide (DETA-NO) attenuated the P/E adhesion response to LPS, whereas the NO synthase inhibitor NG-nitro-l-arginine methyl ester or eNOS deficiency resulted in an exacerbation. P/E adhesion response did not differ between LPS-treated WT and inducible NOS-deficient mice. Inhibition of sGC abolished the attenuating effects of DETA-NO, whereas the sGC activator 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) reduced LPS-induced P/E adhesion. These findings indicate that 1) eNOS-derived NO attenuates endotoxin-induced P/E adhesion and 2) sGC is responsible for the antiadhesive action of NO.

5-Hydroxytryptamine- and U46619-mediated vasoconstriction in bovine pulmonary conventional and supernumerary arteries: effect of endogenous nitric oxide

1999 ◽  
Vol 98 (1) ◽  
pp. 81-89 ◽  
Author(s):  
D. BUNTON ◽  
A. MACDONALD ◽  
T. BROWN ◽  
A. TRACEY ◽  
J. C. MCGRATH ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Guanylate Cyclase ◽  
Vascular Tone ◽  
No Synthase ◽  
Vasoconstrictor Response ◽  
Cgmp Pathway ◽  
Endogenous Nitric Oxide ◽  
Synthase Inhibitor ◽  
Resting Tone

We compared 5-hydroxytryptamine (5-HT)- and U46619-mediated contractions in bovine pulmonary conventional arteries (CA) and supernumerary arteries (SA). The effects of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (100 μM) and the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 μM) on the responses of CA and SA to 5-HT and U46619 were also examined. In addition, the effects of the 5-HT2B receptor antagonist SB 200646 (1 nM–1 μM) on the responses to 5-HT in SA and CA were studied. Tissue cGMP levels were measured in the absence and presence of l-NAME, ODQ, 5-HT and U46619. 5-HT was approximately 30 times more potent in SA {-log [EC50 (M)] (pEC50) 6.32±0.13} than in CA (5.05±0.14). U46619 displayed a similar potency in both CA (pEC50 7.80±0.07) and SA (7.75±0.12). l-NAME did not significantly alter the resting tone of CA or SA. In contrast, ODQ produced a transient increase in the tone of both CA and SA. Neither l-NAME nor ODQ altered the responses to 5-HT or U46619 in CA. In addition, neither l-NAME nor ODQ altered the responses to U46619 in SA, but both l-NAME and ODQ increased the magnitude of the response to 5-HT in SA without changing the sensitivity. Inhibition of the 5-HT2B receptor with SB 200646 did not alter the response to 5-HT in SA or CA. Basal levels of cGMP (pmol/mg of protein) were similar in CA (1.16±0.33) and SA (0.8±0.51), and were not significantly changed in the presence of 5-HT or U46619. l-NAME and ODQ reduced the basal levels of cGMP in both SA and CA. The results suggest that endogenous NO selectively attenuates the vasoconstrictor response to 5-HT in SA, but not in CA. These results also suggest that the NO/cGMP pathway may have a role in maintaining low vascular tone, but that other mechanisms are able to compensate for the absence of this pathway.

Vasoactivity of the gasotransmitters hydrogen sulfide and carbon monoxide in the chicken ductus arteriosus

2011 ◽  
Vol 301 (4) ◽  
pp. R1186-R1198 ◽  
Author(s):  
Saskia van der Sterren ◽  
Pamela Kleikers ◽  
Luc J. I. Zimmermann ◽  
Eduardo Villamor
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Hydrogen Sulfide ◽  
Guanylate Cyclase ◽  
Vascular Tone ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
No Synthase ◽  
Mechanical Responses ◽  
Synthase Inhibitor

Besides nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is a third gaseous messenger that may play a role in controlling vascular tone and has been proposed to serve as an O2 sensor. However, whether H2S is vasoactive in the ductus arteriosus (DA) has not yet been studied. We investigated, using wire myography, the mechanical responses induced by Na2S (1 μM–1 mM), which forms H2S and HS− in solution, and by authentic CO (0.1 μM-0.1 mM) in DA rings from 19-day chicken embryos. Na2S elicited a 100% relaxation (pD2 4.02) of 21% O2-contracted and a 50.3% relaxation of 62.5 mM KCl-contracted DA rings. Na2S-induced relaxation was not affected by presence of the NO synthase inhibitor l-NAME, the soluble guanylate cyclase (sGC) inhibitor ODQ, or the K+ channel inhibitors tetraethylammonium (TEA; nonselective), 4-aminopyridine (4-AP, KV), glibenclamide (KATP), iberiotoxin (BKCa), TRAM-34 (IKCa), and apamin (SKCa). CO also relaxed O2-contracted (60.8% relaxation) and KCl-contracted (18.6% relaxation) DA rings. CO-induced relaxation was impaired by ODQ, TEA, and 4-AP (but not by l-NAME, glibenclamide, iberiotoxin, TRAM-34 or apamin), suggesting the involvement of sGC and KV channel stimulation. The presence of inhibitors of H2S or CO synthesis as well as the H2S precursor l-cysteine or the CO precursor hemin did not significantly affect the response of the DA to changes in O2 tension. Endothelium-dependent and -independent relaxations were also unaffected. In conclusion, our results indicate that the gasotransmitters H2S and CO are vasoactive in the chicken DA but they do not suggest an important role for endogenous H2S or CO in the control of chicken ductal reactivity.

Functional difference between SP and NKA: relaxation of gastric muscle by SP is mediated by VIP and NO

1993 ◽  
Vol 264 (4) ◽  
pp. G678-G685
Author(s):  
J. G. Jin ◽  
S. Misra ◽  
J. R. Grider ◽  
G. M. Makhlouf
Keyword(s):  
Nitric Oxide ◽  
Circular Muscle ◽  
No Synthase ◽  
No Production ◽  
Neurokinin A ◽  
Functional Difference ◽  
Receptor Agonists ◽  
Gastric Muscle ◽  
Guinea Pig Stomach ◽  
Synthase Inhibitor

The mechanism of action of endogenous tachykinins [substance P (SP) and neurokinin A and B (NKA and NKB)] and of receptor-specific tachykinin analogues (SP methyl ester (SPME), [beta-Ala8]NKA-(4-10), and senktide) was examined in circular muscle of guinea pig stomach. Cross-desensitization studies confirmed that SPME and SP interacted with NK-1 receptors, [beta-Ala8]NKA-(4-10) and NKA with NK-2 receptors, and senktide and NKB with NK-3 receptors. NK-1 and NK-3-receptor agonists induced relaxation and stimulated vasoactive intestinal peptide (VIP) release and nitric oxide (NO) production: tetrodotoxin abolished VIP release, NO production, and relaxation, converting the response to NK-1-receptor agonists to contraction; the NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished NO production, partly inhibited VIP release (56-64%, P < 0.01), and abolished relaxation; the VIP antagonist VIP-(10-28) partly inhibited NO production (73-74%, P < 0.001) and relaxation (56-58%, P < 0.01); and atropine augmented relaxation by 28-35% (P < 0.01). The pattern of inhibition implied that: 1) relaxation was mediated by VIP and NO; 2) VIP release was partly dependent on NO production, since it was strongly inhibited by L-NNA; and 3) NO was largely produced by the action of VIP on muscle cells, since it was strongly inhibited by VIP-(10-28). NK-2-receptor agonists elicited only contraction that was not affected by tetrodotoxin; these agonists also inhibited VIP release, NO production, and relaxation induced by NK-1- and NK-3-receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 93: Hypertension and Renal Injury Induced by Nitric Oxide Depletion are Ameliorated by Concomitant Depletion of Hydrogen Sulfide

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Sebastiaan Wesseling ◽  
Joost O Fledderus ◽  
Johanna A Dijk ◽  
Chantal Tilburgs ◽  
Marianne C Verhaar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Renal Injury ◽  
Renal Damage ◽  
No Synthase ◽  
Tubular Epithelium ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Synthase Inhibitor

Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease is associated with decreased NO availability and less renal H 2 S production. We hypothesized that combined depletion of NO and H 2 S aggravates hypertension and renal injury. Male 8-wk old Sprague Dawley rats were treated with vehicle, NO synthase inhibitor L-NG-nitroarginine (LNNA; 125 mg/L in drinking water), cystathionine-γ-lyase (CSE) inhibitor propargylglycine (PAG; 37.5 mg/kg BW ip daily) or LNNA + PAG for 1 and 4 weeks (6 rats/group). LNNA after 4w increased systolic blood pressure (SBP; 223±10 vs . 137±3 mmHg in controls; P<0.01), proteinuria (144±35 vs. 17±2 mg/d; P<0.01), uremia (16.6±4.2 vs . 7.0±0.4 mmol/L; P<0.05) and tubulo-interstitial injury (P<0.01). LNNA reduced urinary NO metabolite (NOx) excretion by ∼85% after 1w and 4w. PAG alone had no effect on SBP, renal function or injury, but did reduce urinary NOx excretion. Co-treatment with PAG ameliorated LNNA-induced hypertension (182±10 mmHg; P<0.01) and prevented proteinuria (27±3 mg/d), uremia (8.3±0.4 mmol/L) and tubulo-interstitial injury, but did not further reduce urinary NOx excretion. Renal H 2 S production was almost absent in all PAG groups after 1w and 4w (P<0.01) and was reduced in LNNA-treated rats after 4w (4.6±1.4 vs . 9.2±0.5 μmol/hr/mg; P<0.01). Renal HO-1 gene expression was strongly induced in all PAG-treated groups after 1w and 4w (4 to 19-fold; P<0.01) whereas LNNA only increased HO-1 gene expression at 4w (P<0.01). Immunohistochemistry showed that renal HO-1 protein was primarily interstitial in all PAG-treated groups at 1w and 4w. In contrast, LNNA only showed HO-1 in tubular epithelium in conjunction with protein casts. Depleting NO caused hypertension and renal damage followed by reduced renal H 2 S production and increased renal HO-1 expression. Surprisingly, concomitant inhibition of CSE ameliorated hypertension and prevented renal injury. PAG almost completely blocked renal H 2 S production and caused strong induction of renal HO-1, independently of injury, suggesting that H 2 S suppresses renal HO-1 expression. In conclusion, concomitant upregulation of HO-1 expression by inhibition of H 2 S production, prevents LNNA-induced hypertension and renal injury.

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