Repeated but not acute exposure with a low dose range of the nitric oxide (NO) donor sodium nitroprusside (SNP) induces anxiolytic-like behaviour in a dose-independent manner in two different rat models of anxiety

We hypothesized that nitric oxide (NO) contributes to intrasplenic fluid extravasation by inducing greater relaxation in splenic resistance arteries than veins such that intrasplenic microvascular pressure (PC) rises. Fluid efflux was estimated by measuring the difference between splenic blood inflow and outflow. Intrasplenic infusion of the NO donor S-nitroso- N-acetylpenicillamine (SNAP) (0.3 μg · 10 μl−1 · min−1) caused a significant increase in intrasplenic fluid efflux (baseline: 0.8 ± 0.4 ml/min, n = 10 vs. peak rise during SNAP infusion: 1.3 ± 0.4 ml/min, n = 10; P < 0.05). Intrasplenic PC was measured in the isolated, blood-perfused rat spleen. Intrasplenic infusion of SNAP (0.1 μg · 10 μl−1 · min−1) caused a significant increase in PC (saline: 10.9 ± 0.2 mmHg, n = 3 vs. SNAP: 12.2 ± 0.2 mmHg, n = 3; P < 0.05). Vasoreactivity of preconstricted splenic resistance vessels to sodium nitroprusside (SNP) (1 × 10−12-1 × 10−4 M) and SNAP (1 × 10−10-3 × 10−4 M) was investigated with the use of a wire myograph system. Significantly greater relaxation of arterioles than of venules occurred with both SNP (%maximal vasorelaxation: artery 96 ± 2.3, n = 9 vs. vein 26 ± 1.9, n = 10) and SNAP (%maximal vasorelaxation: artery 50 ± 3.5, n = 11 vs. vein 32 ± 1.7, n = 8). These results are consistent with our proposal that differential vasoreactivity of splenic resistance arteries and veins to NO elevates intrasplenic PC and increases fluid extravasation into the systemic lymphatic system.

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Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00234.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. L205-L213 ◽

Cited By ~ 77

Author(s):

Patrick J. McNamara ◽

Prashanth Murthy ◽

Crystal Kantores ◽

Lilian Teixeira ◽

Doreen Engelberts ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Kinase Inhibitors ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Neonatal Rat ◽

Rock Inhibitor ◽

No Donor ◽

Rat Models ◽

Pulmonary Hemodynamic

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 FiO2, or 1 mg·kg−1·day−1 ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1; 2 μg/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.

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The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00400.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. H2037-H2045 ◽

Cited By ~ 19

Author(s):

Lennart G. Bongartz ◽

Branko Braam ◽

Marianne C. Verhaar ◽

Maarten Jan M. Cramer ◽

Roel Goldschmeding ◽

...

Keyword(s):

Nitric Oxide ◽

Low Dose ◽

Left Ventricular Systolic Dysfunction ◽

Systolic Dysfunction ◽

Systolic Pressure ◽

Left Ventricular ◽

No Synthase ◽

Nitric Oxide Donor ◽

No Production ◽

No Donor

We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with Nω-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 ± 3% vs. 37 ± 2% in Veh-treated rats, P < 0.001) and stroke volume (324 ± 33 vs. 255 ± 15 μl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 ± 1.1 mmHg) than Veh-treated rats (16.3 ± 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 ± 1.8 vs. 30.9 ± 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload.

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Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish

10.1101/576942 ◽

2019 ◽

Author(s):

K. Chhabria ◽

A. Vouros ◽

C. Gray ◽

R.B. MacDonald ◽

Z. Jiang ◽

...

Keyword(s):

Nitric Oxide ◽

Sodium Nitroprusside ◽

Optic Tectum ◽

Neurovascular Unit ◽

Cell Number ◽

Neuronal Activation ◽

Negative Effects ◽

Mural Cell ◽

No Donor ◽

Glucose Exposure

AbstractDiabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood, and currently no treatment exists to prevent these negative effects. We previously found that the NO donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish and the ability of SNP to prevent these.We incubated 4 days post fertilisation (dpf) zebrafish embryos in 20mM glucose or mannitol for five days until 9dpf, with or without 0.1mM SNP co-treatment for 24h (8-9dpf), and quantified vascular nitric oxide reactivity, vascular mural cell number, expression of aklf2areporter, glial fibrillary acidic protein (GFAP) and TRPV4, as well as spontaneous neuronal activation at 9dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies.We find that glucose exposure significantly reduced nitric oxide reactivity,klf2areporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour we found glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure.Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype, and function of the optic tectum and on whole organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.

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Regulation of an inwardly rectifying K+ channel by nitric oxide in cultured human proximal tubule cells

AJP Renal Physiology ◽

10.1152/ajprenal.00014.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. F411-F417 ◽

Cited By ~ 9

Author(s):

Kazuyoshi Nakamura ◽

Junko Hirano ◽

Manabu Kubokawa

Keyword(s):

Nitric Oxide ◽

Protein Kinase ◽

Low Dose ◽

Specific Inhibitor ◽

High Dose ◽

Channel Activity ◽

No Donor ◽

Proximal Tubule Cells ◽

Tubule Cells ◽

Inwardly Rectifying

We investigated the effects of nitric oxide (NO) on activity of the inwardly rectifying K+ channel in cultured human proximal tubule cells, using the cell-attached mode of the patch-clamp technique. An inhibitor of NO synthases, Nω-nitro-l-arginine methyl ester (l-NAME; 100 μM), reduced channel activity, which was restored by an NO donor, sodium nitroprusside (SNP; 10 μM) or 8-bromo-cGMP (8-BrcGMP; 100 μM). However, SNP failed to activate the channel in the presence of an inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μM). Similarly, the SNP effect was abolished by a protein kinase G (PKG)-specific inhibitor, KT-5823 (1 μM), but not by a protein kinase A-specific inhibitor, KT-5720 (500 nM). Another NO donor, S-nitroso- N-acetyl-d,l-penicillamine (10 μM), mimicked the SNP-induced channel activation. In contrast to the stimulatory effect of SNP at a low dose (10 μM), a higher dose of SNP (1 mM) reduced channel activity, which was not restored by 8-BrcGMP. Recordings of membrane potential with the slow whole cell configuration demonstrated that l-NAME (100 μM) and the high dose of SNP (1 mM) depolarized the cell by 10.1 ± 2.6 and 9.2 ± 1.0 mV, respectively, whereas the low dose of SNP (10 μM) hyperpolarized it by 7.1 ± 0.7 mV. These results suggested that the endogenous NO would contribute to the maintenance of basal activity of this K+ channel and hence the potential formation via a cGMP/PKG-dependent mechanism, whereas a high dose of NO impaired channel activity independent of cGMP/PKG-mediated processes.

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Dual effect of nitric oxide on cytosolic Ca2+concentration and insulin secretion in rat pancreatic β-cells

AJP Cell Physiology ◽

10.1152/ajpcell.00223.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. C1215-C1222 ◽

Cited By ~ 38

Author(s):

Yukiko Kaneko ◽

Tomohisa Ishikawa ◽

Satoshi Amano ◽

Koichi Nakayama

Keyword(s):

Nitric Oxide ◽

Insulin Secretion ◽

Kinase Inhibitor ◽

Soluble Guanylate Cyclase ◽

Β Cells ◽

Pancreatic Β Cells ◽

Dual Effect ◽

Independent Manner ◽

No Donor ◽

Isolated Rat

In isolated rat pancreatic β-cells, the nitric oxide (NO) donor NOC-7 at 1 μM reduced the amplitude of the oscillations of cytosolic Ca2+ concentration ([Ca2+]c) induced by 11.1 mM glucose, and at 10 μM terminated them. In the presence of N G-nitro-l-arginine (l-NNA), however, NOC-7 at 0.5 and 1 μM increased the amplitude of the [Ca2+]c oscillations, although the NO donor at 10 μM still suppressed them. Aqueous NO solution also had a dual effect on the [Ca2+]c oscillations. The soluble guanylate cyclase inhibitor LY-83583 and the cGMP-dependent protein kinase inhibitor KT5823 inhibited the stimulatory effect of NO, and 8-bromo-cGMP increased the amplitude of the [Ca2+]c oscillations. Patch-clamp analyses in the perforated configuration showed that 8-bromo-cGMP inhibited whole cell ATP-sensitive K+ currents in the isolated rat pancreatic β-cells, suggesting that the inhibition by cGMP of ATP-sensitive K+ channels is, at least in part, responsible for the stimulatory effect of NO on the [Ca2+]c oscillations. In the presence ofl-NNA, the glucose-induced insulin secretion from isolated islets was facilitated by 0.5 μM NOC-7, whereas it was suppressed by 10 μM NOC-7. These results suggest that NO facilitates glucose-induced [Ca2+]c oscillations of β-cells and insulin secretion at low concentrations, which effects are mediated by cGMP, whereas NO inhibits them in a cGMP-independent manner at high concentrations.

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Polyamine Induction in Postharvest Banana Fruits in Response to NO Donor SNP Occurs via l-Arginine Mediated Pathway and Not via Competitive Diversion of S-Adenosyl-l-Methionine

Antioxidants ◽

10.3390/antiox8090358 ◽

2019 ◽

Vol 8 (9) ◽

pp. 358 ◽

Cited By ~ 3

Author(s):

Veeresh Lokesh ◽

Girigowda Manjunatha ◽

Namratha S. Hegde ◽

Mallesham Bulle ◽

Bijesh Puthusseri ◽

...

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Sodium Nitroprusside ◽

Arginine Decarboxylase ◽

No Donor ◽

Expression Studies ◽

Common Precursor ◽

Competitive Action ◽

Gene Expression Studies

Nitric oxide (NO) is known to antagonize ethylene by various mechanisms; one of such mechanisms is reducing ethylene levels by competitive action on S-adenosyl-L-methionine (SAM)—a common precursor for both ethylene and polyamines (PAs) biosynthesis. In order to investigate whether this mechanism of SAM pool diversion by NO occur towards PAs biosynthesis in banana, we studied the effect of NO on alterations in the levels of PAs, which in turn modulate ethylene levels during ripening. In response to NO donor sodium nitroprusside (SNP) treatment, all three major PAs viz. putrescine, spermidine and spermine were induced in control as well as ethylene pre-treated banana fruits. However, the gene expression studies in two popular banana varieties of diverse genomes, Nanjanagudu rasabale (NR; AAB genome) and Cavendish (CAV; AAA genome) revealed the downregulation of SAM decarboxylase, an intermediate gene involved in ethylene and PA pathway after the fifth day of NO donor SNP treatment, suggesting that ethylene and PA pathways do not compete for SAM. Interestingly, arginine decarboxylase belonging to arginine-mediated route of PA biosynthesis was upregulated several folds in response to the SNP treatment. These observations revealed that NO induces PAs via l-arginine-mediated route and not via diversion of SAM pool.

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

Biochemical Journal ◽

10.1042/bj20050565 ◽

2005 ◽

Vol 390 (2) ◽

pp. 625-631 ◽

Cited By ~ 14

Author(s):

Antonius C. F. Gorren ◽

Michael Russwurm ◽

Alexander Kollau ◽

Doris Koesling ◽

Kurt Schmidt ◽

...

Keyword(s):

Nitric Oxide ◽

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Soret Band ◽

Flavin Mononucleotide ◽

Independent Manner ◽

No Donor ◽

No Release ◽

Glycerol Trinitrate ◽

Haem Protein

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

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Acute and repeated exposure with the nitric oxide (NO) donor sodium nitroprusside (SNP) differentially modulate responses in a rat model of anxiety

Nitric Oxide ◽

10.1016/j.niox.2017.05.002 ◽

2017 ◽

Vol 69 ◽

pp. 56-60 ◽

Cited By ~ 4

Author(s):

Martha A. Orfanidou ◽

Anastasios Lafioniatis ◽

Aikaterini Trevlopoulou ◽

Ntilara Touzlatzi ◽

Nikolaos Pitsikas

Keyword(s):

Nitric Oxide ◽

Sodium Nitroprusside ◽

Rat Model ◽

Repeated Exposure ◽

No Donor

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The Nitric Oxide (NO) Donor Sodium Nitroprusside (SNP) and Its Potential for the Schizophrenia Therapy: Lights and Shadows

Molecules ◽

10.3390/molecules26113196 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3196

Author(s):

Elli Zoupa ◽

Nikolaos Pitsikas

Keyword(s):

Nitric Oxide ◽

Sodium Nitroprusside ◽

Cognitive Deficits ◽

Negative Symptoms ◽

Mental Disease ◽

No Production ◽

No Donor ◽

No Donors ◽

Worldwide Population ◽

The Brain

Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, to develop novel neuroleptics with higher efficacy and safety. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, appears to be implicated in the pathogenesis of schizophrenia. In particular, underproduction of this gaseous molecule is associated to this mental disease. The latter suggests that increment of nitrergic activity might be of utility for the medication of schizophrenia. Based on the above, molecules able to enhance NO production, as are NO donors, might represent a class of compounds candidates. Sodium nitroprusside (SNP) is a NO donor and is proposed as a promising novel compound for the treatment of schizophrenia. In the present review, we intended to critically assess advances in research of SNP for the therapy of schizophrenia and discuss its potential superiority over currently used neuroleptics.

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