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

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.275.5.g1185 ◽

1998 ◽

Vol 275 (5) ◽

pp. G1185-G1192 ◽

Cited By ~ 8

Author(s):

Raj K. Goyal ◽

Xue D. He

Keyword(s):

Nitric Oxide ◽

Potassium Channel ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Slow Component ◽

Circular Muscle ◽

Exact Nature ◽

Channel Blockers ◽

Inhibitory Neurotransmitter ◽

Ly 83583

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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Inhibitory effects on human eosinophil chemotaxis in vitro by BAY 41-2272, an activator of nitric oxide-independent site of soluble guanylate cyclase

Biochemical Pharmacology ◽

10.1016/j.bcp.2004.12.007 ◽

2005 ◽

Vol 69 (6) ◽

pp. 875-882 ◽

Cited By ~ 10

Author(s):

Sara M. Thomazzi ◽

Juliana Moreira ◽

Gilberto De Nucci ◽

Edson Antunes

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Inhibitory Effects ◽

Human Eosinophil ◽

Eosinophil Chemotaxis ◽

Independent Site

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BAY41-2272, a Novel Nitric Oxide Independent Soluble Guanylate Cyclase Activator, Relaxes Human and Rabbit Corpus Cavernosum In Vitro

The Journal of Urology ◽

10.1097/00005392-200302000-00081 ◽

2003 ◽

pp. 761-766 ◽

Cited By ~ 1

Author(s):

JAS S. KALSI ◽

ROWLAND W. REES ◽

ADRIAN J. HOBBS ◽

MICHAEL ROYLE ◽

PHIL D. KELL ◽

...

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Corpus Cavernosum ◽

Rabbit Corpus Cavernosum ◽

Guanylate Cyclase Activator ◽

Cyclase Activator

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Regulation of Sertoli Cell Tight Junction Dynamics in the Rat Testis via the Nitric Oxide Synthase/Soluble Guanylate Cyclase/3′,5′-Cyclic Guanosine Monophosphate/Protein Kinase G Signaling Pathway: an in Vitro Study

Endocrinology ◽

10.1210/en.2002-0167 ◽

2003 ◽

Vol 144 (7) ◽

pp. 3114-3129 ◽

Cited By ~ 87

Author(s):

Nikki P. Y. Lee ◽

C. Yan Cheng

Keyword(s):

Nitric Oxide ◽

Protein Kinase ◽

Tight Junction ◽

Sertoli Cell ◽

Guanylate Cyclase ◽

Barrier Function ◽

Soluble Guanylate Cyclase ◽

Protein Kinase G ◽

Camp And Cgmp

Abstract Nitric oxide (NO) synthase (NOS) catalyzes the oxidation of l-arginine to NO. NO plays a crucial role in regulating various physiological functions, possibly including junction dynamics via its effects on cAMP and cGMP, which are known modulators of tight junction (TJ) dynamics. Although inducible NOS (iNOS) and endothelial NOS (eNOS) are found in the testis and have been implicated in the regulation of spermatogenesis, their role(s) in TJ dynamics, if any, is not known. When Sertoli cells were cultured at 0.5–1.2 × 106 cells/cm2 on Matrigel-coated dishes or bicameral units, functional TJ barrier was formed when the barrier function was assessed by quantifying transepithelial electrical resistance across the cell epithelium. The assembly of the TJ barrier was shown to associate with a significant plummeting in the levels of iNOS and eNOS, seemingly suggesting that their presence by producing NO might perturb TJ assembly. To further confirm the role of NOS on the TJ barrier function in vitro, zinc (II) protoporphyrin-IX (ZnPP), an NOS inhibitor and a soluble guanylate cyclase inhibitor, was added to the Sertoli cell cultures during TJ assembly. Indeed, ZnPP was found to facilitate the assembly and maintenance of the Sertoli cell TJ barrier, possibly by inducing the production of TJ-associated proteins, such as occludin. Subsequent studies by immunoprecipitation and immunoblotting have shown that iNOS and eNOS are structurally linked to TJ-integral membrane proteins, such as occludin, and cytoskeletal proteins, such as actin, vimentin, and α-tubulin. When the cAMP and cGMP levels in these ZnPP-treated samples were quantified, a ZnPP-induced reduction of intracellular cGMP, but not cAMP, was indeed detected. Furthermore, 8-bromo-cGMP, a cell membrane-permeable analog of cGMP, could also perturb the TJ barrier dose dependently similar to the effects of 8-bromo-cAMP. KT-5823, a specific inhibitor of protein kinase G, was shown to facilitate the Sertoli cell TJ barrier assembly. Cytokines, such as TGF-β and TNF-α, known to perturb the Sertoli cell TJ barrier, were also shown to stimulate Sertoli cell iNOS and eNOS expression dose dependently in vitro. Collectively, these results illustrate NOS is an important physiological regulator of TJ dynamics in the testis, exerting its effects via the NO/soluble guanylate cyclase/cGMP/protein kinase G signaling pathway.

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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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Endothelium-dependent regulation of cerebrovascular tone by extracellular and intracellular ATP

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.2.h878 ◽

1997 ◽

Vol 273 (2) ◽

pp. H878-H885 ◽

Cited By ~ 5

Author(s):

D. Janigro ◽

T. S. Nguyen ◽

J. Meno ◽

G. A. West ◽

H. R. Winn

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Smooth Muscle ◽

Guanylate Cyclase ◽

No Synthase ◽

Synthesis Inhibitor ◽

Vascular Responses ◽

Dependent Component ◽

Ly 83583

ATP receptors and ATP-sensitive potassium channels (KATP) are expressed in vascular smooth muscle (VSM) and endothelial cells (EC). In isolated penetrating vessels, ATP caused a dilatation when applied intraluminally but not extraluminally. The actions of ATP were blocked by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine (0.1 mM) but were only reduced by N-monomethyl-L-arginine (0.1 mM); responses to intraluminal ATP were also prevented by thapsigargin. The KATP opener (KCO) nicorandil (1 microM) caused an NO-independent vasodilatation when applied extraluminally and an NO-dependent response when applied intraluminally. Both responses were blocked by glibenclamide. EC-mediated responses to nicroandil were prevented by blockade of guanylate cyclase by LY-83583 (10 microM). The effects of nicorandil were mimicked by pinacidil (1-10 microM). Exposure of the endothelium to 500 microM cyanide and 0 mM glucose ("in vitro ischemia") caused a vasodilatation that was reduced by exposure to glibenclamide (5 microM). Blockade of NO synthase produced similar effects, suggesting that the ischemic dilation is mediated by KATP and NO. Our results suggest that both VSM and EC mediate the vascular responses induced by KCOs, whereas the dilatation induced by intraluminal ATP is mediated by the endothelium. The endothelium-dependent component of the in vitro ischemic vasodilatation is mediated by opening of endothelial KATP and subsequent release of NO.

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