Evidence for NO ⋅ redox form of nitric oxide as nitrergic  inhibitory neurotransmitter in gut

A nitric oxide (NO)-like product of thel-arginine NO synthase pathway has been shown to be a major inhibitory neurotransmitter that is involved in the slow component of the inhibitory junction potential (IJP) elicited by stimulation of nonadrenergic, noncholinergic nerves. However, the exact nature of the nitrergic transmitter, the role of cGMP, and the involvement of a potassium or a chloride conductance in the slow IJP remain unresolved. We examined the effects of soluble guanylate cyclase inhibitors LY-83583 and 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ), potassium-channel blockers and putative chloride-channel blockers diphenylamine-2-carboxylate (DPC) and niflumic acid (NFA) on the hyperpolarization elicited by an NO ⋅ donor, diethylenetriamine/NO adduct (DNO), NO in solution, and an NO+ donor, sodium nitroprusside (SNP), in the guinea pig ileal circular muscle. Effects of these blockers on purinergic (fast) and nitrergic (slow) IJP were also examined. DNO-induced hyperpolarization and nitrergic slow IJP were suppressed by LY-83583 or ODQ and DPC or NFA but not by the potassium-channel blocker apamin. In contrast, hyperpolarization caused by SNP or solubilized NO gas and purinergic fast IJP were antagonized by apamin but not by inhibitors of guanylate cyclase or chloride channels. These results demonstrate biological differences in the actions of different redox states of NO and suggest that NO ⋅ is the nitrergic inhibitory neurotransmitter.

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Nitric oxide-mediated excitatory effect on neurons of dorsal motor nucleus of vagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.266.1.g154 ◽

1994 ◽

Vol 266 (1) ◽

pp. G154-G160 ◽

Cited By ~ 10

Author(s):

R. A. Travagli ◽

R. A. Gillis

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Spontaneous Discharge ◽

Motor Nucleus ◽

Excitatory Effect ◽

Dorsal Motor Nucleus ◽

Ly 83583 ◽

Spontaneous Firing Rate

The purpose of our study was to explore whether nitric oxide was involved as an intercellular messenger in the dorsal motor nucleus of the vagus (DMV). To achieve this purpose we examined DMV motoneurons of the rat in vitro with the use of the extracellular cell-attached recording technique. The motoneurons, in general, exhibit a spontaneous discharge and when exposed to NO-producing drugs (i.e., 3-300 microM L-arginine and 10-100 microM S-nitroso-N-acetylpenicillamine) exhibit a concentration-related increase in their spontaneous firing rate. Because NO activates soluble guanylate cyclase and increases guanosine 3',5'-cyclic monophosphate (cGMP), we tested dibutyryl-cGMP (30-300 microM) and found that it also excites DMV neurons. Perfusion of the DMV neurons with N omega-nitro-L-arginine (300 microM), an inhibitor of NO synthase (NOS), and with NO scavenger, reduced hemoglobin (1 microM), counteracted the excitatory effect of L-arginine and N-methyl-D-aspartate (NMDA). Perfusion of the preparation with LY-83583 (10 microM), an inhibitor of guanylate cyclase, also counteracted the effects of L-arginine and NMDA. These data indicate that NOS is present in DMV neurons, and that the excitatory effect of NMDA on these neurons is due in part to formation of NO and the resulting accumulation of cGMP in DMV neurons.

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Interleukin 1 and endotoxin activate soluble guanylate cyclase in vascular smooth muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1990.259.1.r38 ◽

1990 ◽

Vol 259 (1) ◽

pp. R38-R44 ◽

Cited By ~ 5

Author(s):

D. Beasley

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Interleukin 1 ◽

Physiological Salt Solution ◽

Initial Exposure ◽

Vasodilatory Action ◽

Ly 83583

Our recent studies indicate that interleukin 1 (IL-1) and bacterial lipopolysaccharide inhibit agonist-induced contractions in rat aortic rings by an endothelium-independent mechanism. The present study investigated the role of guanosine 3',5'-cyclic monophosphate (cGMP) in the vasodilatory action of IL-1 and endotoxin. Rat aortic rings were denuded of endothelium and incubated for 3 h in physiological salt solution containing no additions, IL-1 (20 ng/ml), or endotoxin (10 micrograms/ml). Contractions induced by phenylephrine (3 x 10(-7) M) were decreased by 40 and 85% in endotoxin- and IL-1-treated rings, respectively. IL-1 increased cGMP content 2.5-fold in the absence of and 5.5-fold in the presence of 3-isobutyl-1-methylxanthine (IBMX). Endotoxin also increased cGMP content in the absence and presence of IBMX (5.5- and 25-fold, respectively). Both IL-1- and endotoxin-induced increases in cGMP occurred 3-4 h after initial exposure. The guanylate cyclase inhibitors, LY 83583 and methylene blue, each abolished IL-1- and endotoxin-induced inhibition of contraction and IL-1-induced production of cGMP. Furthermore, hemoglobin, which binds nitric oxide, completely blocked IL-1-induced increases in cGMP. We conclude that IL-1 and endotoxin inhibit vascular contraction in vitro by increasing aortic cGMP content. Studies with inhibitors suggest IL-1 and endotoxin may induce endothelium-independent production of nitric oxide or another free radical that activates soluble guanylate cyclase.

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Effects of potassium channel inhibitors in the forced swimming test: Possible involvement of l-arginine-nitric oxide-soluble guanylate cyclase pathway

Behavioural Brain Research ◽

10.1016/j.bbr.2005.06.031 ◽

2005 ◽

Vol 165 (2) ◽

pp. 204-209 ◽

Cited By ~ 74

Author(s):

M KASTER ◽

P FERREIRA ◽

A SANTOS ◽

A RODRIGUES

Keyword(s):

Nitric Oxide ◽

Potassium Channel ◽

Guanylate Cyclase ◽

Forced Swimming Test ◽

Soluble Guanylate Cyclase ◽

Forced Swimming ◽

Swimming Test

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PGE2 and PGI2 inhibit ET-1 secretion from endothelial cells by stimulating particulate guanylate cyclase

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.4.h1342 ◽

1996 ◽

Vol 270 (4) ◽

pp. H1342-H1349 ◽

Cited By ~ 1

Author(s):

M. Razandi ◽

A. Pedram ◽

T. Rubin ◽

E. R. Levin

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Endothelial Cell ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Bovine Aortic Endothelial Cell ◽

Intact Cells ◽

Fourfold Increase ◽

Pg E2 ◽

Ly 83583

Prostaglandins (PG)E2 and prostacyclin (PGI2) can cause vasodilation in selective vascular beds and could act in part by inhibiting the production of the vasoconstrictor endothelin-1 (ET-1). We recently reported that these prostanoids inhibit ET-1 production/secretion from cultured endothelial cells via the generation of guanosine 3'-5'-cyclic monophosphate (cGMP). It is unclear whether this results from the stimulation of the particulate (membrane) of soluble (cytosolic) form of guanylate cyclase, and whether these effects are through an intermediate, such as nitric oxide. PGE2 and PGI2 each caused a three- to fourfold increase in both membrane and whole bovine aortic endothelial cell guanylate cyclase activity. The stimulations were significantly reversed (80-90%) by the compound LY-83583, an antagonist to cGMP generation, but were unaffected by methylene blue (MB), an inhibitor of nitric oxide-induced soluble guanylate cyclase. In contrast, the prostaglandins did not generate cGMP in cytosolic fractions. The prostaglandins inhibited ET-1 secretion from the intact cells, which was significantly prevented by LY-83583, but not by MB. Neither prostaglandin stimulated NO synthase activity, an indicator of nitric oxide generation. We conclude that PGE2 and PGI2 are likely to inhibit ET-1 secretion through the activation of the particulate guanylate cyclase, identifying a novel mechanism by which the prostanoids signal in the endothelial cell.

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